Difluoroprostacyclins

ABSTRACT

A difluoroprostacyclin of the following formula (V), its lower alkanol ester or its pharmaceutically acceptable salt: ##STR1## wherein A is an ethylene group, a vinylene group or an ethynylene group, R is a substituted or unsubstituted C 1-10  alkyl group, a substituted or unsubstituted C 1-10  alkenyl group, a substituted or unsubstituted C 1-10  alkynyl group, a substituted or unsubstituted C 3-8  cycloalkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxy group, Q is a substituted or unsubstituted C 1-10  alkyl group, a substituted or unsubstituted C 1-10  alkenyl group, a substituted or unsubstituted C 1-10  alkynyl group, a substituted or unsubstituted C 3-8  cycloalkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group.

The present invention relates to novel difluoroprostacyclins. Moreparticularly, it relates to 7,7-difluoroprostacyclins having twofluorine atoms at the 7-position of prostacyclin.

Natural type prostacyclin (PGI₂) is a local hormone exhibiting strongphysiological activities such as platelet aggregation inhibitoryactivities, vasodilation activities or cytophylatic activities, in vivo,and it is an important factor for adjusting cellular functions in vivo.However, natural type prostacyclin will be easily deactivated underneutral or acidic condition (the half-life in an aqueous solution ofpH7.48 at 25° C. is 10.5 minutes), since it hats a readily decomposablevinyl ether bond in its molecule. Attempts have been made to developsuch prostacyclin as medicines, but due to the chemical instability, itsapplication area as medicines has been limited in many cases.Accordingly, studies are being made to develop a prostacyclin derivativewhich has the same physiological activities as natural prostacyclin andwhich is chemically stable.

Prostacyclins having fluorine atoms at the 7-position have been reported(Japanese International Patent Application No. 501319/1981, JapaneseUnexamined Patent Publications No. 165382/1982, No. 171988/1982, No.91136/1986, No. 482/1987 and No. 9184/1993, and Japanese Examined PatentPublications No. 14030/1991, No. 272/1991 and No. 24147/1989).

In the following description, the positional numbers for carbon atoms inprostacyclins or their intermediates will be represented by thepositional numbers for carbon atoms in the corresponding natural typeprostacyclin, unless otherwise specified. Accordingly, for example, the7-position means the position corresponding to the 7-position of naturaltype prostacyclin irrespective of the presence or absence of an a-chainor its length.

With respect to prostacyclins having two or more fluorine atoms,Japanese International Publication No. 501319/1981 disclosesprostacyclins fluorinated at the 2-position, the 4-position, the7-position or the 10-position. However, with respect to the physicalproperty data, the specific rotatory power is disclosed only for10,10-difluoro-13,14-dehydroprostacyclin, and no physiological activitydata is given for any compounds. Among such prostacyclins having two ormore fluorine atoms, 10,10-difluoro-13,14-dehydroprostacyclin is theonly compound, of which the physiological activities have been madeclear. J. Fried et al. as the inventors for the invention disclosed inthe above Japanese International Patent Publication No. 501319/1981,have reported on the vasodilation activities, platelet aggregationinhibitory activities, chemical stabilities, etc. in e.g. J. Med. Chem.,23, 234 (1980) Proc. Natl. Acad. Sci. USA, 77, 6846 (1980) and Thromb.Res. 23, 387 (1981).

On the other hand, with respect to prostacyclins having two fluorineatoms at the 7-position, a Preparation Example for7,7-difluoro-13,14-dehydroprostacyclin is disclosed in theabove-mentioned Japanese International Patent Publication No.501319/1981, but the synthesis used in the Example is considered to bepractically really difficult to carry out, and no physical data orphysiological activity data is disclosed, and so far as the presentinventors are aware, there has been no further report since then.Further, among difluoroprostacyclins, there is no preparation exampleother than the one in which the 13- and 14-positions of the ω-chain areof a dehydro type, and no Preparation Example has been known forderivatives in which the 16- to 20-positions are other than a n-pentylgroup, such as a branched alkyl group, an alkenyl group, an alkynylgroup or a cycloalkyl group.

7,7-difluoro-13,14-dehydroprostacyclin disclosed in the PreparationExample of the above-mentioned Japanese International Patent PublicationNo. 501319/1981, is prepared in such a manner that using cyclopentadieneand dichloro ketone as starting materials,7,7-difluoro-13,14-dehydroprostagrandin F₂ is firstly synthesized andthen cyclized. In this method, preparation of the material i.e.7,7-difluoro-13,14-dehydroprostagrandin F₂ requires a plurality of stepsand is very difficult. In particular, the Wittig Reaction to prepare7,7-difluoro-13,14-dehydroprostagrandin F₂ by reacting5-triphenylphosphonopentanoic acid to the corresponding hemiacetalhaving two electron-withdrawing fluorine atoms as adjacent groups, willbe practically difficult to obtain the desired product, since, as isdifferent from the usual case, the yield in the reaction will remarkablybe lowered by the strong electron-withdrawing effects of the fluorineatoms. Further, the cyclization reaction of7,7-difluoro-13,14-dehydroprostagrandine F₂ has problems that since twoelectron-withdrawing fluorine atoms are present adjacent to the olefinas the reaction site, the reactivity is very low, it requires a longtime for the reaction, and the yield in the reaction is low, as isdifferent from the cyclization reaction of natural type prostagrandinF₂. Thus, the process is practically very difficult.

As described above, with respect to conventional7,7-difluoroprostacyclins, no specific physical data or physiologicalactivity data have been known, and it is hardly believable that suchcompounds have actually been synthesized.

The present inventors have conducted studies with an aim to actuallyprepare 7,7-difluoroprostacyclins and then measure their physicalproperties and physiological activities to study their usefulness asmedicines and to find out difluoroprostacyclins which are chemicallystable and which have physiological activities similar to natural typeprostacyclin. As a result, the present inventors have succeeded indeveloping a process for producing 7,7-difluoroprostacyclins, which isdifferent from the above-mentioned process, whereby they have succeededin synthesizing novel difluoroprostacyclins and in discoveringdifluoroprostacyclins which have high physiological activities and whichare chemically stable.

The present invention relates to difluoroprostacyclins and a process fortheir production. Further, the present invention relates to novelintermediates useful for such a process and to processes for suchintermediates. Now, the basic production scheme and its generalstructure will be described first, and then the compounds involved inthe scheme and the processes for their production will be described indetail.

Basic production scheme

The basic scheme for production of difluoroprostacyclins of the presentinvention is as follows: ##STR2##

The formulas (VI) and (VII) are combined and represented by thefollowing formula (XI). Likewise, the formulas (I) and (II) are combinedand represented by the following formula (XII); the formulas (I) and(III) are combined and represented by the following formula (XIII); theformulas (II) and (IV) are combined and represented by the followingformula (XIV); and the formulas (III) and (IV) are combined andrepresented by the following formula (XV). ##STR3## General structure ofthe basic production scheme

In the above production scheme, the difluoroprostacyclins of the presentinventions are compounds of the formula (IV). Among thedifluoroprostacyclins of the formula (IV), preferred compounds aredifluoroprostacyclins of the formula (V).

The difluoroprostacyclins of the formula (IV) of the present inventioncan be produced by introducing the α-chain moiety to difluorolactones ofthe formula (II) having the ω-chain moiety introduced. Otherwise, theycan be produced by introducing the ω-chain moiety to bicyclo compoundsof the formula (III) having the α-chain moiety introduced. Thedifluorolactones of the formula (II) having the ω-chain moietyintroduced, can be prepared by introducing the ω-chain moiety todifluorolactones of the formula (I). Likewise, the bicyclo compounds ofthe formula (III) having the α-chain moiety introduced, can be producedby introducing the α-chain moiety to the difluorolactones of the formula(I). The difluorolactones of the formula (I) are novel compounds.

The difluorolactones of the formula (I) can be prepared by fluorinatinglactones of the formula (VI). The difluorolactones of the formula (II)having the ω-chain moiety introduced, can be prepared by fluorinatinglactones of the formula (VII) having the ω-chain moiety introduced. Thelactones of the formula (VII) having the ω-chain moiety introduced, canbe prepared by introducing the ω-chain moiety to lactones of the formula(VI).

Introduction of the α-chain moiety

Introduction of the α-chain moiety is meant for conversion of ═O of thelactone moiety to ═CH-Q. The introduction of the α-chain moietycorresponds to the step of producing two compounds of the formula (XV)in the third stage of the basic scheme from two compounds of the formula(XII) in the second stage of the basic scheme.

As a first method, an organometallic compound of the formula (VIII) isaddition-reacted to a compound having a lactone structure, followed bydehydration. In this case, it is usually necessary that the hydroxylgroups in the compound having a lactone structure are protected (i.e.R¹, R² and R³ are protecting groups).

    (Q-CH.sub.2).sub.m ML.sub.n                                (VIII)

As a second method for introducing the α-chain moiety, the desiredcompound can also be produced by reacting a phosphorane of the followingformula (XVI).

    Q-CH═P(R.sup.7).sub.3                                  (XVI)

This second method is simpler than the above-mentioned first method andpresents a high yield, and since no by-product from the metalliccompound will be produced, the purification is easy. Also in the case ofthis second method, it is usually necessary that the hydroxyl groups inthe compound having a lactone structure are protected.

Introduction of the ω-chain moiety

Introduction of the ω-chain moiety is meant for converting -CH₂ OR² to-A-CH(OR₃)-R. The introduction of the ω-chain moiety corresponds to thestep of producing two compounds of the formula (XIV) on the right handside of the basic scheme from two compounds of the formula (XIII) on theleft hand side of the basic scheme. Further, the stage of producing acompound of the formula (VII) at the upper right hand side from acompound of the formula (VI) at the upper left hand side, is alsointroduction of the ω-chain moiety.

As a method for this introduction, the desired compound can be producedby converting -CH₂ OR² to -CHO, and reacting the product with an organicphosphonate of the formula (IX), followed by reduction. In this case, itis usually necessary that functional groups such as hydroxyl groups inthe compound having -CH₂ OR² are protected (i.e. R¹, etc. are protectinggroups).

    (R.sup.4 O).sub.2 (P═O)CH.sub.2 (C═O)R             (IX)

Fluorination

By fluorinating a lactone of the formula (VI) or a lactone of theformula (VII) having the ω-chain moiety introduced, it is possible toproduce a difluoro compound having two fluorine atoms at the 7-position,i.e. a difluorolactone of the formula (I) or a difluorolactone of theformula (II) having the ω-chain moiety introduced. Namely, thisfluorination corresponds to the step of producing two compounds of theformula (XII) in the second stage from two compounds of the formula (XI)in the first stage of the basic scheme.

This fluorination is preferably conducted by reacting an electrophilicfluorinating agent in the presence of a metal compound (X) under a basiccondition.

The fluorination in the present invention can be carried out in a singlestep or in two steps. The fluorination in a single step means tointroduce two fluorine atoms simultaneously. Likewise, the fluorinationin two steps means to introduce the two fluorine atoms separately i.e.one after the other. A monofluoro compound having one fluorine atomintroduced to the lactone of the formula (VI) and a monofluoro compoundhaving one fluorine atom introduced to the lactone of the formula (VII)having the ω-chain moiety introduced, are basically known compounds. Byintroducing one fluorine atom to such monofluoro compounds, it ispossible to obtain the corresponding difluoro compounds.

Terms

In the following description, the term "lower" for an organic groupcorresponds to a carbon number of from 1 to 6. A preferred lower organicgroup is an organic group having from 1 to 4 carbon atoms. An "alkylgroup" may be a straight chain or branched, and unless otherwisespecified, a lower alkyl group is preferred. Specific examples include amethyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a t-butyl group, a pentyl group and ahexyl group. An "alkenyl group" is preferably a lower alkenyl groupunless otherwise specified, more preferably a straight chain or branchedalkenyl group having from 2 to 6 carbon atoms and one unsaturated group.Specific examples include a vinyl group, allyl group, a 1-propenylgroup, an isopropenyl group, a 3-butenyl group, a 3-pentenyl group and a4-hexenyl group. An "alkynyl group" is preferably a lower alkynyl groupunless otherwise specified, more preferably a straight chain or branchedalkynyl group having from 2 to 6 carbon atoms and one unsaturated group.Specific examples include a 1-propynyl group, a 2-propynyl group, anisopropynyl group, a 3-butynyl group, a 3-pentinyl group and a 4-hexynylgroup.

As an "alkoxy group", a lower alkoxy group is preferred, and morepreferred is a straight chain or branched alkoxy group having from 1 to4 carbon atoms. Specific examples include a methoxy group, an ethoxygroup, a propoxy group and a butoxy group. As an "alkoxyalkyl group", alower alkyl group wherein the alkoxy moiety is a lower alkoxy group.Specific examples include a 2-methoxyethyl group, a 3-methoxypropylgroup and a 2-ethoxyethyl group.

A "halogen atom" means a fluorine atom, a chlorine atom, a bromine atomor an iodine atom. An "aryl group" means a monovalent aromatichydrocarbon group which may have a substituent (such as a lower alkylgroup, a halogen atom, a lower alkoxy group or a lower alkylaminogroup), preferably a phenyl group or its derivatives. For example, aphenyl group, a tolyl group, a p-halophenyl group (such as ap-chlorophenyl group or a p-bromophenyl group), or an alkoxyphenyl group(such as a methoxyphenyl group or an ethoxyphenyl group) may bementioned. An "aralkyl group" means an aryl-substituted alkyl group, inwhich the aryl group as the substituent may be as described above, andthe carbon number of the alkyl group is preferably from 1 to 4. Specificexamples include a benzyl group, a (2-methylphenyl)methyl group, a(3-methylphenyl)methyl group, a (3-ethylphenyl)methyl group, abenzhydryl group, a trityl group and a phenetyl group. Preferred aralkylgroups are a benzyl group and a (3-methylphenyl)methyl group.

A "protecting group" is a group for provisionally protecting afunctional group having a reactivity such as a hydroxyl group, acarboxyl group or a formyl group. Functional groups are usually requiredto be protected in intermediates used for the production of desiredfinal products. For example, R¹ or R³ is usually required to be aprotecting group until the final desired compound of adifluoroprostacyclin (IV) or (V) is produced. The lower alkanol residuein the lower alkanol ester in the difluoroprostacyclin (V) may beregarded as a protecting group for a carboxyl group. In the final use asa medicine, this ester is usually converted to a hydrogen atom or acation. Known protecting groups which are commonly used can be used assuch protecting groups.

A protecting group for protecting a hydroxyl group (a protecting groupfor a hydroxyl group) is not particularly limited. Known or well knownprotecting groups used as protecting groups for a hydroxyl group may beemployed. Such protecting groups may be the same or different. Theprotecting groups for a hydroxyl group include, for example, atriorganosilyl group, an acyl group, an alkyl group, an aralkyl group ora cyclic ether group. Such protecting groups are suitably employeddepending upon the particular purpose. For example, when it is requiredto selectively remove only one of the two protecting groups from acompound, it is preferred to use protecting groups having differentreactivities. Specifically, R² and R³ are preferably triorganosilylgroups, while R¹ is preferably a cyclic ether group or a triorganosilylgroup (when other protecting groups are triorganosilyl groups, the onehaving a reactivity different from them).

The triorganosilyl group is a group having three organic groups such asalkyl groups, aryl groups, aralkyl groups or alkoxy groups bonded to asilicon atom. Particularly preferred is a triorganosilyl group havingthree groups of at least one kind selected from the group consisting oflower alkyl groups and aryl groups. Specifically, a t-butyldimethylsilylgroup, a t-butyldiphenylsilyl group, a triethylsilyl group, atriphenylsilyl group or a triisopropylsilyl group may, for example, bepreferred.

As the acyl group, an acetyl group or a benzoyl group is preferred, andas the cyclic ether group, a tetrahydropyranyl group or atetrahydrofuranyl group is preferred. As the alkyl group which may havea substituent or the aralkyl group, an alkoxyalkyl group such as amethoxymethyl group, a 1-ethoxyethyl group or a 2-methoxyethoxymethylgroup as well as a benzyl group, a methoxybenzyl group or a trityl groupmay, for example, be mentioned.

The protecting group for a hydroxyl group as mentioned above, can beconverted to a hydroxyl group by a conventional method. For example, itcan readily be converted to a hydroxyl group by methods disclosed ine.g. "Shinjikken Kagaku Koza 14 Syntheses and Reactions of OrganicCompounds (I), (II) and (V)", published by Maruzen, and "ProtectiveGroups in Organic Synthesis" edited by T. W. Greene, J. Wiley & Sons.

Difluorolactones (I) ##STR4##

In the above formula (I), each of R¹ and R² which are independent ofeach other is a hydrogen atom or a protecting group.

The difluorolactone of the formula (I) in the present invention is apreferred compound as a starting compound of a difluoroprostacyclin ofthe formula (IV). In this compound, each of R¹ and R² may be a hydrogenatom, but is usually required to be a protecting group for thesubsequent reaction. This difluorolactone of the formula (I) can beprepared by fluorinating a lactone of the formula (VI). As mentionedabove, R¹ is preferably a cyclic ether group or a triorganosilyl grouphaving a reactivity different from R², and R² is preferably atriorganosilyl group or an acyl group.

As mentioned above, the difluorolactone of the formula (I) can beproduced by fluorinating a lactone of the formula (VI). It isparticularly preferred to produce it by the following fluorinationmethod of introducing two fluorine atoms in one step. However, it can beproduced by fluorination in two steps. Further, the difluorolactone ofthe formula (I) may be produced by other methods (Japanese InternationalPatent Publication NO. 501319/1981).

Details of fluorination

Now, the method for producing the difluorolactone of the formula (I) byfluorinating a lactone of the formula (VI) will be described in detail.This fluorination method can be applied also to a fluorination methodfor producing the difluorolactone of the formula (II) having the ω-chainmoiety introduced from the lactone of the formula (VII) having theω-chain moiety introduced. This difluoro conversion may be representedby the following formula In the following formula, R⁵ is -CH₂ OR² or-A-CH(OR³)-R. The compound of the formula (XI) represents both thelactone of the formula (VI) and the lactone of the formula (VII) havingthe ω-chain moiety introduced. Likewise, the compound of the formula(XII) represents both the difluorolactone of the formula (I) and thedifluorolactone of the formula (II) having the ω-chain moietyintroduced. ##STR5##

As a method for producing the difluorolactone of the formula (I) bydifluorination of the lactone of the formula (VI), it is preferred toemploy a method of reacting an electrophilic fluorinating agent in thepresence of a metal compound (X). This difluorination reaction ispreferably conducted under a basic condition and in the presence of aninert solvent. The metal compound (X) is believed to activate an activesubstance formed in an intermediate stage of the reaction with respectto the fluorination reaction. If the fluorination is conducted in theabsence of the metal compound, a difluoro compound will notsubstantially form although a monofluoro compound may form.

Metal compound (X)

As the metal compound (X), an organometallic compound or a metal saltmay, 5or example, be mentioned. As the metal in the metal compound, ametal species such as B, Mg, Al, Ca, Ti, V, Mn, Fe, Co, Ni, Cu, Zn, Zr,Sn, Ba, Hf, W, La, Ce or Sm may, for example, be mentioned. As the metalcompound (X), a metal halide, an organic metal halide (particularly analkyl metal halide), a metallocene halide, or a metal salt oftrifluoromethanesulfonic acid is, for example, preferred. As the metalspecies, a transition metal is preferred. As specific metal compounds(X), the following metal compounds may, for example, be mentioned.

Boron trifluoride etherate, magnesium chloride, magnesium bromide,magnesium iodide, magnesium trifluoromethanesulfonate, aluminumchloride, dialkyl aluminum chloride, alkylaluminum dichloride, calciumchloride, titanium tetrachloride, titanium trichloride isopropoxide,titanium dichloride diisopropoxide, titanium chloride triisopropoxide,titanium tetrabromide, titanium tribromide isopropoxide, titaniumdibromide diisopropoxide, titanium bromide triisopropoxide, titanocenedichloride, vanadium chloride, manganese dichloride, manganesedibromide, iron trichloride, iron tribromide, iron triiodide, cobaltchloride, nickel chloride, nickel bromide, copper chloride, copperbromide, copper iodide, zinc chloride, zinc bromide, zinc iodide, zinctrifluoromethanesulfonate, zirconium chloride, zirconium bromide,zirconocene dichloride, zirconocene chloride hydride, tin tetrachloride,tin dichloride, tin trifluoromethanesulfonate, ballium chloride, balliumbromide, ballium iodide, hafnium chloride, hafnocene dichloride,tangusten chloride, lanthanum chloride, cerium chloride, and samariumiodide.

The metal compound is used usually in an amount of from 0.01 to 20equivalents, preferably from 0.1 to 10 equivalents, per equivalent ofthe lactone of the formula (VI).

Electrophilic fluorinating agent

The electrophilic fluorinating agent is not particularly limited. Knownor well known electrophilic fluorinating agents may be employed. Forexample, electrophilic fluorinating agents disclosed, for example, in"Fluorine Chemistry" edited by Tomoya Kitazume, Takashi Ishihara andTakeo Taguchi and published by Kodansha Scientific, may, for example, beused. Specifically, fluorine gas, xenon fluoride, perchloryl fluoride,acetyl hypofluorite, N-fluorosulfonamides, or N-fluorosulfonimides may,for example, be mentioned. N-fluorosulfonamides or N-fluorosulfonimidesare preferred. Specifically, N-fluorobenzenesulfonimide,N-fluoro-p-fluorobenzenesulfonimide, N-fluoro-o-benzenedisulfonimide,N-fluoro-p-toluenesulfonimide, N-fluoro-N-t-butylbenzenesulfonamide,N-fluoro-N-t-butyl-p-toluenesulfonamide,N-fluoro-N-methylbenzenesulfonamide, andN-fluoro-N-norbornyl-p-fluorobenzenesulfonamide are particularlypreferred.

The electrophilic fluorinating agent is used usually in an amount offrom 0.5 to 20 equivalents, preferably from 2 to 10 equivalents, perequivalent of the lactone of the formula (VI).

Basic condition

As the base, an amide of an alkali metal such as lithium, sodium orpotassium with ammonia or a secondary amine, a hydride of an alkalimetal, an alkali metal alkoxide or an organic compound of an alkalimetal is, for example, preferred. Specifically, lithium amide, sodiumamide, potassium amide, lithium diisopropylamide, lithium diethylamide,lithium dicyclohexylamide, lithium isopropylcyclohexylamide,lithium-2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilazide,sodium diethylamide, sodium hexamethyldisilazide,potassium-3-aminopropylamide, potassium hexamethyldisilazide, lithiumhydride, sodium hydride, potassium hydride, potassium t-butoxide,n-butyl lithium, s-butyl lithium, t-butyl lithium, lithium naphthalenideor lithium biphenylide may, for example, be mentioned.

The base is used usually in an amount of from 0.5 to 20 equivalents,preferably from 2 to 10 equivalents, per equivalent of the lactone ofthe formula (VI).

Inert solvent

As the inert solvent, an ether solvent, a hydrocarbon solvent, a polarsolvent, or a solvent mixture thereof is preferred. The ether solventmay, for example, be diethyl ether, tetrahydrofuran, 1,4-dioxan,1,2-dimethoxyethane, diglyme or t-butylmethyl ether. The hydrocarbonsolvent may, for example, be hexane, toluene, benzene, pentane, xyleneor petroleum ether. The polar solvent may, for example, bedimethylsulfoxide, hexamethylphosphoramide (HMPA),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolydinone (DMI), orN,N,N',N'-tetramethylethylenediamine (TMEDA). The inert solvent is usedusually in an amount of from 5 to 1,000 parts by weight, preferably from10 to 100 parts by weight, per part by weight of the lactone of theformula (VI). The reaction temperature for the above fluorinationreaction is usually from -150° to +100° C., preferably from -80° to +40°C.

Monofluorinated products

A monofluorinated product of the lactone of the formula (VI) and amonofluorinated product of the lactone of the formula (VII) having theω-chain moiety introduced are basically known compounds (JapaneseUnexamined Patent Publication No. 171988/1982). By fluorinating suchmonofluoro compounds, it is possible to produce the correspondingdifluoro compounds, i.e. the difluorolactones of the formula (I) and thedifluorolactone of the formula (II) having the ω-chain moietyintroduced.

The above monofluoro compounds can be produced by a conventional method.Further, according to the above-mentioned fluorination method, the abovemonofluoro compound can be produced under a milder condition by using aless amount of the fluorination agent, by using a fluorination agentother than those mentioned above, or by using a reactant other than theabove-mentioned metal compound (X) or a catalyst. As the method forproducing a difluoro compound by fluorinating the monofluorinatedproduct, it is preferred to employ the above-mentioned fluorinationmethod.

Difluorolactones of the formula (II) having the ω-chain moietyintroduced ##STR6##

In the above formula (II), A, R, R³ are as follows (R¹ is as definedabove).

A: An ethylene group, a vinylene group or an ethynylene group

R: A substituted or unsubstituted C₁₋₁₀ alkyl group, a substituted orunsubstituted C₁₋₁₀ alkenyl group, a substituted or unsubstituted C₁₋₁₀alkynyl group, a substituted or unsubstituted C₃₋₈ cycloalkyl group, asubstituted or unsubstituted aralkyl group, or a substituted orunsubstituted aryloxy group.

R³ : A hydrogen atom or a protecting group for a hydroxyl group.

As A, a vinylene group or an ethynylene group is preferred, andparticularly preferred is a vinylene group. OR³ bonded to the carbonatom at the 15-position may be present below the paper surface or abovethe paper surface. In natural type PGI₂, the hydroxyl group bonded atthe 15-position is present below the paper surface. The compound whereint:his hydroxyl group is present above the paper surface, has nosubstantial physiological activities. However, the difluoroprostacyclinsof the formulas (IV) and (V) of the present invention have a remarkablecharacteristic such that not only the compounds wherein the hydroxylgroup bonded at the 15-position is present below the paper surface, butalso the compounds wherein the hydroxyl group is present above the papersurface, have physiological activities.

With respect to R

R is preferably an organic group corresponding to the ω-chain moiety ofnatural type PGI₂ or an organic group corresponding to the ω-chainmoiety of various PGI₂. Such an organic group includes, for example, aC₁₋₁₀ alkyl group, a C₁₋₁₀ alkenyl group, a C₁₋₁₀ alkynyl group, a C₃₋₈cycloalkyl group, an aryloxy group having an aryl group such as a phenylgroup, and such groups having various substituents. The substituentsmay, for example, be a cycloalkyl group and an aryl group. For example,the organic group may be a cycloalkyl group-substituted alkyl group, acycloalkyl group-substituted alkenyl group, or an aryl group-substitutedalkenyl group. Further, it may be an organic group having a carbon atomof a chain organic group substituted by an oxygen atom or a sulfur atom,or an organic group having a ring such as a cycloalkylene group or anarylene group in the chain organic group. Substituents in R include, inaddition to the above-mentioned substituents, a halogen atom, an oxygenatom-containing substituent, a sulfur atom-containing substituent, anitrogen atom-containing substituent, and others.

Among the above-mentioned various groups, a chain hydrocarbon group ispreferred as R. The chain hydrocarbon group is preferably a C₃₋₈ alkylgroup, a C₃₋₈ alkenyl group or a C₃₋₈ alkynyl group. Particularlypreferred is such a group of a linear type with 5 or 6 carbon atoms orits monomethyl or dimethyl-substituted group.

When R is a chain hydrocarbon group, the carbon number of the linearmoiety excluding any branch is preferably 5 or 6. Further, such a linearmoiety may have one unsaturated double bond or unsaturated triple bond.The branch moiety is preferably a methyl group or an ethyl group, andparticularly preferred is a methyl group. There may be two or morebranched moieties, preferably one or two branched moieties. The twobranched moieties may be bonded to one carbon atom. Such a branchedmoiety is bonded preferably at the 1- to 3-position of the chainhydrocarbon group, more preferably at the 1- or 2-position. In such acase, an unsaturated double bond or unsaturated triple bond ispreferably present at 3- or subsequent position.

Specific chain hydrocarbon groups include the following groups:

A n-butyl group, a n-pentyl group, a n-hexyl group, a n-heptyl group, an-octyl group, a n-decyl group, a 1-methylpentyl group, a1,1-dimethylpentyl group, a 1-methylhexyl group, a 2-methylpentyl group,a 2-methylhexyl group, a 3-pentenyl group, a 1-methyl-3-pentenyl group,a 1-methyl-3-hexenyl group, a 1,1-dimethyl-3-pentenyl group, a1,1-dimethyl-3-hexenyl group, a 2-methyl-3-pentenyl group, a2-methyl-3-hexenyl group, a 3-pentynyl group, a 1-methyl-3-pentynylgroup, a 1-methyl-3-hexynyl group, a 2-methyl-3-pentynyl group, a2-methyl-3-hexynyl group, a 1,1-dimethyl-3-pentynyl group, and a1,1-dimethyl-3-hexynyl group.

Among the above chain hydrocarbon groups, preferred are a 2-methylpentylgroup, a 1-methylhexyl group, a 2-methylhexyl group, a1,1-dimethylpentyl group, a 1-methyl-3-pentynyl group, a1-methyl-3-hexynyl group, and a 1,1-dimethyl-3-hexynyl group.Particularly preferred are a 2-methylhexyl Group and a1-methyl-3-hexynyl group.

The substituted or unsubstituted cycloalkyl group for R is preferably aC₃₋₈ cycloalkyl group, or such a cycloalkyl group substituted by a loweralkyl group. Particularly preferred is an unsubstituted cyclopentylgroup, an unsubstituted cyclohexyl group, a C₁₋₄ alkyl group-substitutedcyclopentyl group, or a C₁₋₄ alkyl group-substituted cyclohexyl group.

The substituted or unsubstituted aralkyl group for R is preferably anaralkyl group containing, for example, a benzene ring, a furan ring, athiophene ring or a naphthalene ring substituted by, for example, alower alkyl group, a halogen atom, a halogenated alkyl group, an alkoxygroup or a hydroxyl group. The carbon number of the alkyl moiety (i.e.the alkylene group) of the aralkyl group is preferably from 1 to 4. Aparticularly preferred aralkyl group is a C₁₋₂ alkyl group having atolyl group.

The substituted or unsubstituted aryloxy group for R is preferably anaryloxy group containing, for example, a benzene ring, a furan ring, athiophene ring or a naphthalene ring substituted, for example, by ahalogen atom, a halogenated alkyl group, an alkoxy group or a hydroxylgroup. Particularly preferred aryloxy group is a phenoxy group.

As R other than those described above, a C₁₋₄ alkyl group substituted bythe above-mentioned cycloalkyl group is preferred as one type of asubstituted alkyl group. As such a cycloalkyl group, a cyclopentyl groupor a cyclohexyl group is preferred, and as such an alkyl group, a C₁₋₂alkyl group is preferred.

Process for producing difluorolactones of the formula (II) having theω-chain moiety introduced

The difluorolactones of the formula (II) having the ω-chain moietyintroduced, can be prepared by introducing the ω-chain moiety todifluorolactones of the formula (I). Otherwise, they can be prepared byfluorinating lactones of the formula (VII) having the ω-chain moietyintroduced. The following method is preferred as a method forintroducing the ω-chain moiety.

The lactones of the formula (VII) having the ω-chain moiety introduced,can be prepared by introducing the ω-chain moiety to the lactones of theformula (VI). The method for its introduction is also preferably thefollowing method.

Details for introduction of the ω-chain moiety

A method for introducing the ω-chain moiety will be described in detailwith reference to a process for producing a difluorolactone of theformula (II) having the ω-chain moiety introduced, from adifluorolactone of the formula (I). This method for introducing theω-chain moiety can be applied also to a process for producing adifluoroprostacyclin of the formula (IV) from a bicyclo compound of theformula (III) having the α-chain moiety introduced. Likewise, thismethod for introducing the ω-chain moiety can be applied also to aprocess for producing a lactone of the formula (VII) having the ω-chainmoiety introduced, from a lactone of the formula (VI).

Introduction of the ω-chain moiety may be represented by the followingformulas, in which R⁶ is an oxygen atom of the formula ═O, or a bivalentorganic group of the formula ═CH-Q. The compound of the formula (XIII)represents both of the difluorolactone of the formula (I) and thebicyclo compound of the formula (III) having the α-chain moietyintroduced, and the compound of the formula (XIV) represents both of thedifluorolactone of the formula (II) having the ω-chain moietyintroduced, and the difluoroprostacyclin of the formula (IV). ##STR7##

Introduction of the ω-chain moiety is preferably carried out by aWittig-Horner-Emmons Reaction which is a known reaction. Namely, amethod is preferred in which -CH₂ OR² is converted to -CHO, and theproduct is reacted with an organic phosphonate of the formula (IX),followed by reduction. In this case, it is usually necessary thatfunctional groups such as a hydroxyl group, etc. in the startingmaterial are protected (i.e., R¹, etc. are protecting groups).

    (R.sup.4 O).sub.2 (P═O)CH.sub.2 (C═O)R             (IX)

In the above formula (IX), R is as defined above, and R⁴ is a loweralkyl group. R⁴ is preferably an alkyl group having at most 4 carbonatoms, more preferably a methyl group or an ethyl group.

Oxidation reaction

The reaction to convert -CH₂ OR² to -CHO is an oxidation reaction toconvert an alcohol to an aldehyde. When R² is a hydrogen atom, oxidationcan directly be applied to convert -CH₂ OR² to -CHO. When R² is aprotecting group, R² is selectively subjected to the reaction to removethe protecting group to convert it to a hydrogen atom, and thenoxidation can be conducted in the same manner. The reaction to removethe protecting group for R² differs depending upon the structure of R²,and conventional methods and conditions for reactions to removeprotecting groups can be applied. For example, when R¹ is atetrahydropyranyl group or an acetyl group, and R² is at-butyldimethylsilyl group, it is possible to selectively subject onlyR² to the reaction to remove the protective group by using tetrabutylammonium fluoride or HF-pyridine.

The oxidation reaction is usually carried out in the presence of e.g.dimethylsulfoxide, trifluoroacetic acid, pyridine anddicyclohexylcarbodiimide at a temperature of from -50° C. to +50° C.,preferably from 0° to +25° C. with stirring.

Reaction with an organic phosphonate of the formula (IX)

The reaction of the aldehyde compound formed by the oxidation reaction,with the organic phosphonate of the formula (IX) is usually preferablycarried out in the presence of sodium hydride and dimethoxyethane. Thereaction temperature is usually from -50° C. to +50° C., preferably from0° C. to +50° C. By this reaction, ω-chain is connected, and anunsaturated ketone will be formed at the connected portion.

Reduction reaction

The above unsaturated ketone is reduced, whereby a difluorolactone ofthe formula (II) having the ω-chain moiety introduced (provided that Ais a vinylene group) will be formed. This reduction is usuallypreferably carried out in methanol in the presence of sodium borohydrideand cerium trichloride. The reaction temperature is usually from -100°C. to +50° C., preferably from -80° C. to +10° C.

The compound wherein A is an ethylene group, can be prepared by reducingthe unsaturated ketone by a method of reducing by means of a metalhydride such as lithium aluminum hydride or a method of hydrogenation.Otherwise, it can be prepared by converting the unsaturated ketone to asaturated ketone by a method of a 1,4-reduction reaction using a copperhydride reactant, such as (tributyltin) copper lithium hydride or copperhydride triphenylphosphine complex, followed by reduction.

The compound wherein A is an ethynylene group can be prepared by theabove-mentioned reaction of the aldehyde with the organic phosphonate ofthe formula (IX) in the presence of a halogenating agent such asN-bromosuccinic acid imide or N-chlorosuccinic imide, and furthertreating with a strong base such as potassium-t-butoxide.

The bicyclo compound of the formula (III) having the α-chain moietyintroduced ##STR8##

In the formula (III), Q is as defined below (R¹ and R² are as definedabove).

Q: A substituted or unsubstituted C₁₋₁₀ alkyl group, a substituted orunsubstituted C₁₋₁₀ alkenyl group, a substituted or unsubstituted C₁₋₁₀alkynyl group, a substituted or unsubstituted C₃₋₈ cycloalkyl group,substituted or unsubstituted aralkyl group, or a substituted orunsubstituted aryl group.

With respect to Q

Q is preferably an organic group corresponding to the α-chain of naturaltype PGI₂, or an organic group corresponding to the α-chain of variousPGI₂. As such an organic group, a C₁₋₁₀ alkyl group, a C₁₋₁₀ alkenylgroup, a C₁₋₁₀ alkynyl group, a C₃₋₈ cycloalkyl group, an aryl groupsuch as a phenyl group, and such groups having various substituents, maybe mentioned. As the substituents, a cycloalkyl group and an aryl groupmay be mentioned. Such groups may, for example, be a cycloalkylgroup-substituted alkyl group, a cycloalkyl group-substituted alkenylgroup, and an aryl group-substituted alkenyl group. Further, it may bean organic group having a carbon atom of a chain organic groupsubstituted by an oxygen atom or a sulfur atom, or an organic grouphaving a ring such as a cycloalkylene group or an arylene group in achain organic group.

The substituents in Q include, in addition to the above-mentionedsubstituents, a halogen atom, an oxygen atom-containing substituent, asulfur atom-containing substituent, a nitrogen atom-containingsubstituent, etc. Preferred Q is an organic group having a polarsubstituent such as a carboxyl group, or a group which can be convertedto such a polar substituent, at its terminal. As the polar substituent,an oxygen atom-containing polar substituent (a carboxyl group, a formylgroup and a hydroxyl group are preferred), and a group which can beconverted to such a substituent, are preferred. Particularly preferredis a carboxyl group and a group which can be converted to a carboxylgroup. Particularly preferred Q is an organic group represented by theafter-mentioned formula -B-Z having Z as a polar substituent or asubstituent which can be converted to a polar substituent.

Except for the case of the final difluoroprostacyclins of the formula(IV) having physiological activities, Q is preferably Q having a groupconvertible to a carboxyl group at its terminal, so that it is inert inthe reactions in the course to arrive at such final compounds. Namely, Qin the organometallic compound of the formula (VIII) as well as in thebicyclo compounds of the formula (III) having the α-chain moietyintroduced and the difluoroprostacyclin of the formula (IV) justsynthesized, is preferably Q having a group convertible to a carboxylgroup at its terminal. After the difluoroprostacyclin of the formula(IV) has been produced, this Q is converted to Q having a terminalcarboxyl group. As described hereinafter, even in a case where Q is agroup of the formula -B-Z, Z in the organometallic compound of theformula (VIII) is preferably a group convertible to a polar substituent,and after reaching to the difluoroprostacyclin of the formula (IV), thisZ is converted to a polar substituent, particularly to a carboxyl group.

With respect to -B-Z

Q is preferably a monovalent organic group of the formula -B-Z. Z is apolar group or a group which can be converted to a polar group (such asa protected polar group), and B is a bivalent organic group. Z ispreferably a carboxyl group, a group which can be converted to acarboxyl group (hereinafter referred to as an analogous group to acarboxyl group), a formyl group, a protected formyl group, a hydroxylgroup, or a protected hydroxyl group. Except for the case of a finaldesired compound among difluoroprostacyclins of the formula (IV) (i.e. adihalogenated prostacyclin having physiological activities), Z ispreferably an analogous group to a carboxyl group. In the final desiredcompound, Z is most preferably a carboxyl group or a group of its salt.Usually, after synthesizing a difluoroprostacyclin of the formula (IV)wherein Z is an analogous group to a carboxyl group, which is thenconverted to a salt of a carboxyl group, as the case requires. Further,also when Z is a formyl group, a protected formyl group, a hydroxylgroup or a protected hydroxyl group, it is preferred that Z is finallyconverted to a carboxyl group.

When Z is a protected formyl group, various protecting groups may beemployed as the protecting group, but a protecting group such as anacetal or a thioacetal is preferred. When Z is a protected hydroxylgroup, various protecting groups may be employed for the protectinggroup, but the above-mentioned protecting groups for a hydroxyl groupare suitably employed.

When Z is an analogous group to a carboxyl group, the analogous group toa carboxyl group may, for example, be a carboxyl group neutralized witha base, an esterified carboxyl group, an orthoesterified carboxyl group,an amide-modified carboxyl group, or a carboxyl group protected by e.g.a tetrazole or a nitrile. Preferred analogous groups for a carboxylgroup are an esterified carboxyl group, an orthoesterified carboxylgroup, and a carboxyl group protected by a tetrazole. As the esterifiedcarboxyl group, a carboxyl group esterified with a lower alkanol,particularly an alkoxy carbonyl group wherein the alkyl moiety is a C₁₋₄alkyl group, is preferred. As the ortho esterified carboxyl group, anorthoester with a lower alkanol, or an orthoester with an alkanetriol,is preferred. As the alkanetriol, trimethylol ethane, trimethylolpropane or glycerol may, for example, be mentioned. As the tetrazole,1H-tetrazole or 2H-tetrazole is preferred.

As Z, particularly preferred is an esterified or orthoesterifiedcarboxyl group which is stable in the reactions for preparing adifluoroprostacyclin of the formula (IV) and which is an analogous groupto a carboxyl group, which can be readily converted to a carboxyl groupafter completion of the reactions.

When Z is the above-mentioned group other than the carboxyl group or itssalt, such Z can be converted to a carboxyl group by a conventionalreaction for converting to a functional group, such as by a reaction toremove a protecting group, hydrolysis or an oxidation reaction. Such aconversion can be carried out by methods disclosed, for example, in"Shinjikken Kagaku Koza, 14, Syntheses and Reactions of OrganicCompounds (I), (II) and (V), Maruzen" or "Protective Groups in OrganicSynthesis, edited by T. W. Greene, J. Wiley & Sons".

B is a residue obtained by removing the above Z from the above Q, and itis preferably a lower alkylene group, a lower cycloalkylene group, alower alkylene group containing a lower cycloalkylene group (thealkylene group may be present at each side of the cycloalkylene group),a lower alkylene group containing an ether bond or a thioether bond, ora phenylene group. Particularly preferred is a C₃₋₅ alkylene group, aC₃₋₆ cycloalkylene group, a C₁₋₄ alkylene group containing a C₃₋₆cycloalkylene group, a C₂₋₄ alkylene group containing one ether bond orone thioether bond in its intermediate position or a m-phenylene group.Most preferred B is a C₃₋₅ straight chain alkylene group. Specifically,B includes, for example, a trimethylene group, a tetramethylene group, apentamethylene group, a cyclopropylene group, a 1,2-cyclobutylene group,a 1,3-cyclobutylene group, a 1,2-cyclopentylene group, a1,3-cyclopentylene group, a 1,3-cyclohexylene group, a group having amethylene group bonded to one end of such a cycloalkylene group, -CH₂OCH₂ -, -CH₂ SCH₂ -, -(CH₂)₃ OCH₂ -, -(CH₂)₃ SCH₂ -, and an m-phenylenegroup. Most preferred B is a trimethylene group.

Details for introduction of the α-chain moiety

Now, a method for introducing the α-chain moiety will be described indetail with reference to the process for producing adifluoroprostacyclin of the formula (IV) from a difluorolactone of theformula (II) having the ω-chain moiety introduced. This method ofintroducing the α-chain moiety can be applied also to other processesfor introduction of the α-chain moiety. Namely, it can be applied to aprocess for producing a bicyclo compound of the formula (III) having theα-chain moiety introduced, from a difluorolactone of the formula (I).

In a usual addition and dehydration reactions of a lactone having nofluorine atom at the α-position of the carbonyl group, a product havingthe lactone ring opened, will mainly form. However, in the presentreaction wherein a difluoro compound is employed, theelectron-withdrawing nature of fluorine atoms is utilized, so that abicyclo compound having the ring structure maintained, can be producedin good yield. Introduction of the α-chain moiety by this reaction is amethod which does not involve a synthesis of a prostagrandin F₂ having afluorine atom or a ring opening reaction between the 6- and 9-positionsthereof, as was the case in the conventional method. Accordingly, thereaction is easy even if two fluorine atoms are present at the7-position.

Introduction of the α-chain moiety can be represented by the followingformulas.

In the following formulas, R⁵ is -CH₂ OR² or -A-CH(OR³)-R, as mentionedabove. The compound of the formula (XII) represents both of thedifluorolactone of the formula (I) and the difluorolactone of theformula (II) having the ω-chain moiety introduced, as mentioned above.Likewise, the compound of the formula (XV) represents both of thebicyclo compound of the formula (III) having the ω-chain moietyintroduced, and the difluoroprostacyclin of the formula (IV). ##STR9##

Introduction of the α-chain moiety is preferably carried out by addingan organometallic compound of the formula (VIII) to a compound having alactone structure, followed by dehydration. As another method forintroducing the α-chain moiety, a phosphorane of the following formula(XVI) is reacted for the production. This second method is considered tobe advantageous over the first method of using the organometalliccompound of the formula (XIII), as mentioned above.

    Q-CH═P(R.sup.7).sub.3                                  (XVI)

When these reactions are carried out, the hydroxyl groups in thecompound having a lactone structure are usually required to be protected(i.e. R¹, R² and R³ are protecting groups). When free hydroxyl groupsare present, by-products are likely to form, and the reaction tends tohardly proceed. Accordingly, when the difluorolactone of the formula(II) having the ω-chain moiety introduced, prepared by theabove-mentioned method, has free hydroxyl groups, it is necessary toprotect such free hydroxyl groups prior to this reaction. Protection ofhydroxyl groups can be conducted by conventional methods. In the secondmethod, as compared with the first method, it is less necessary toprotect hydroxyl groups, and there may be a case where the reaction canbe conducted even when free hydroxy groups are present.

Method 1 for introducing the α-chain moiety

Organometallic compound of the formula (XlII)

    (Q-CH.sub.2).sub.m ML.sub.n                                (VIII)

In the organometallic compound of the formula (VIII), M is a metal atom,L is a ligand to the metal, and each of m and n is an integer determinedby the type of the metal atom and the type of the ligand, and m is aninteger of from 1 to 8, and n is an integer of from 0 to 10. Preferably,m is from 1 to 4, more preferably from 1 to 2, and n is preferably from0 to 4, more preferably from 0 to 2, and m +n is preferably from 1 to 3.

The metal atom M may be a metal such as lithium, sodium, potassium,magnesium, calcium, boron, aluminum or silicon, or a transition metalsuch as zinc, copper, iron, titanium, zirconium, manganese, tin, cobalt,nickel, cerium or samarium. Among them, lithium, sodium, magnesium,boron, aluminum, zinc or copper is preferred. Particularly preferred Mis lithium, magnesium, aluminum or zinc.

The ligand L to the metal is not particularly limited, and variousligands may be employed. However, a ligand containing a halogen atomsuch as chlorine, bromine, iodine or fluorine, or a hetero atom such assulfur or phosphorus, or an organic ligand such as an alkyl group, anaryl group, an alkenyl group or an alkynyl group is, for example,preferred. Particularly preferred L is chlorine, bromine, a lower alkylgroup (particularly a C₁₋₄ alkyl group), or a phenyl group.

Addition reaction

In the addition reaction of the compound having a lactone structure withthe organometallic compound of the formula (VIII), the organometalliccompound of the formula (VIII) is used usually from 0.1 to 10equivalents, preferably from 0.5 to 3 equivalents, per equivalent of thecompound having a lactone structure. The reaction temperature is usuallyfrom -150° C. to 100° C., preferably from -100° C. to +40° C.

The above addition reaction can usually be conducted in the presence ofa solvent. As the solvent for the reaction, an ether solvent, ahydrocarbon solvent, a polar solvent or a solvent mixture thereof ispreferred. The ether solvent may, for example, be diethyl ether,tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diglyme or t-butylmethylether; the hydrocarbon solvent may, for example, be hexane, toluene,benzene, pentane, xylene or petroleum ether; and the polar solvent may,for example, be dimethylsulfoxide, hexamethylphosphoramide (HMPA),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), orN,N,N',N'-tetramethylethylenediamine (TMEDA)

Dehydration reaction

After the addition reaction, the reaction product is subjected to adehydration reaction to obtain a compound having the α-chain moietyintroduced (both R¹ and R³ are protecting groups).

In the dehydration reaction, various dehydrating agents may be employed.As the dehydrating agents, those disclosed, for example, in "ShinjikkenKagaku Koza, 14, Syntheses and Reactions of Organic Compounds (I)"published by Maruzen, may be employed. For example, an acid catalyst, abase catalyst, a halogenation reagent, a sulfonylation reagent, anesterification reagent, an acid anhydride, alumina, silica or an ionexchange resin may, for example, be mentioned. Specifically, asulfonylation reagent such as methanesulfonyl chloride ortoluenesulfonyl chloride, a dehydration agent such as phosphorylchloride, thionyl chloride, oxalyl chloride, acetyl chloride, acetylbromide, acetic anhydride, phthalic anhydride, phosphorous tribromide,N-bromosuccinimide, iodine, sulfur dioxide, phosphorus pentoxide ordicyclohexylcarbodiimide, or an acid catalyst such as p-toluenesulfonicacid, pyridinium p-toluenesulfonate or sulfuric acid is, for example,preferred.

In this dehydration reaction, the dehydration agent is used usually inan amount of from 0.1 to 10 equivalents, preferably from 1 to 5equivalents, per equivalent of the addition reaction product. In thecase where a base is used in combination, the amount of the base isusually from 0.1 to 10 equivalents, per equivalent of the dehydrationagent. The reaction temperature for the dehydration reaction is usuallyfrom -80° C. to +100° C., and the reaction time is usually from 10minutes to 10 hours.

Such a dehydration agent may be used in combination with an amine suchas triethylamine, diisopropylethyl amine, tributylamine, pyridine,collidine, lutidine, 1,8-diazabicyclo[5.4.0]undeca-7-ene,1,5-diazabicyclo[4.3.0]nona-5-ene or 1,4-diazabicyclo[2.2.2]octane, orwith a base such as sodium acetate, potassium carbonate or sodiummethoxide. It is particularly preferred to use a sulfonylation reagentsuch as methanesulfonyl chloride or toluenesulfonyl chloride as thedehydration agent in combination with an amine such as triethylamine,diisopropylethylamine, tributylamine, pyridine, collidine, lutidine,1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]nona-5-eneor 1,4-diazabicyclo[2.2.2]octane.

Method 2 for introducing the α-chain moiety

Phosphoranes of the formula (XVI)

    Q-CH═P(R.sup.7).sub.3                                  (XVI)

In the phosphorane of the formula (XVI), Q is as defined above, and R⁷is a monovalent organic group.

R⁷ is preferably an aryl group which may have a substituent, an alkylgroup which may have a substituent, an aralkyl group which may have asubstituent, or a dialkylamino group. Particularly preferred is an arylgroup which may have a substituent. As the substituent for the arylgroup, a lower alkyl group, a halogen atom, a lower alkoxy group, alower alkylamino group, a nitro group or a hydroxyl group may, forexample, be mentioned. The substituent for the alkyl group includes suchsubstituents except for the lower alkyl group.

The aryl group which may have a substituent, may, for example, be aphenyl group, a naphthyl group, a tolyl group, a p-chlorophenyl group, ap-bromophenyl group, a p-fluorophenyl group, a p-methoxyphenyl group, ap-ethoxyphenyl group, a p-nitrophenyl group, an o-chlorophenyl group, ano-bromophenyl group, an o-fluorophenyl group, an o-methoxyphenyl group,an o-ethoxyphenyl group or an o-nitrophenyl group. Particularlypreferred is a phenyl group or a tolyl group.

The alkyl group which may have a substituent, is preferably a straightchain or branched alkyl group having not more than 20 carbon atoms.Particularly preferred is a lower alkyl group. Specifically, a straightchain alkyl group such as a methyl group, an ethyl group, a n-propylgroup, a n-butyl group, a n-pentyl group, a n-hexyl group, a n-heptylgroup or a n-octyl group, or a branched alkyl group such as an isopropylgroup, an isobutyl group, a t-butyl group or a neopentyl group is, forexample, preferred. The aralkyl group which may have a substituent, ispreferably an aralkyl group wherein the alkyl moiety (i.e. the alkylenegroup) has from 1 to 4 carbon atoms, and the aryl moiety is a phenylgroup. Particularly preferred is a benzyl group, a phenetyl group or atolyl group.

The dialkylamino group is preferably a dialkylamino group having loweralkyl groups. Specifically, a dimethylamino group, a diethylamino groupor a di(n-butyl)amino group may, for example, be mentioned.

Preparation of phosphoranes of the formula (XVI)

A phosphorane of the formula (XVI) can be prepared by a conventionalmethod from the corresponding phosphonium salt. For example, it can beprepared by reacting the following quaternary phosphonium salt (X⁻ is ananion such as a halogen ion) with a base in an inert solvent.

    [Q-CH.sub.2 -P(R.sup.7).sub.3 ].sup.+ X.sup.-

General methods for producing phosphoranes from phosphonium salts aredisclosed, for example, in the above-mentioned "Shinjikken Kagaku Koza,14. Syntheses and Reactions of Organic Compounds (I), published byMaruzen" and "Fourth Edition of Jikken Kagaku Koza, 19. OrganicSynthesis I, Hydrocarbons-Halogenated Compounds, published by Maruzen".The phosphoranes of the formula (XVI) can be prepared by using suchconventional methods.

A proper type of the base to be used for the preparation of aphosphorane of the formula (XVI) differs depending upon the acidity ofthe α-hydrogen of the phosphonium salt as the starting material of thephosphorane and the stability of the resulting phosphorane. Preferably,the following bases may be mentioned.

Sodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, sodium methoxide, sodium ethoxide, triethylamine,diisopropylethylamine, pyridine, N-methylmorpholine, diazabicyclononene,diazabicycloundecene, potassium t-butoxide, lithium amide, sodium amide,potassium amide, lithium diisopropyl amide, lithium diethyl amide,lithium dicyclohexyl amide, lithium isopropylcyclohexyl amide,lithium-2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilazide,sodium diethylamide, sodium hexamethyldisilazide,potassium-3-aminopropylamide, potassium hexamethyldisilazide, lithiumhydride, sodium hydride, potassium hydride, dimsyl sodium, n-butyllithium, s-butyl lithium, t-butyl lithium, ethyl lithium, phenyllithium, lithium naphthalenide, lithium biphenylide, and trityl sodium.

As the inert solvent, an ether solvent, a hydrocarbon solvent, a polarsolvent, an aqueous solvent, an alcohol solvent or a solvent mixturethereof is preferred. As the ether solvent, the hydrocarbon solvent andthe polar solvent, inert solvents described in the above section for"Details of fluorination" can be used. For this reaction, water, asolvent mixture of water with other solvents, and an alcohol solventsuch as methanol, ethanol, t-butanol or t-amylalcohol, may also be used.

Reaction with the compound of the formula (XII)

The phosphorane of the formula (XVI) is a kind of Wittig Reactionagents. To the reaction system in which the phosphorane of the formula(XVI) has been prepared, a compound of the formula (XII) may be added,so that the two compounds are reacted to each other. Namely, aquaternary phosphonium salt is reacted with a base in an inert solvent,and without separating the resulting phosphorane of the formula (XVI), acompound of the formula (XII) is added to the reaction system, so thatthe two compounds can be reacted. The phosphorane of the formula (XVI)is used usually in an amount of from 0.1 to 20 equivalents, preferablyfrom 1 to 10 equivalents, per equivalent of the compound of the formula(XII). The amount of the base is usually from 0.1 to 20 equivalents,preferably from 1 to 10 equivalents, per equivalent of the compound ofthe formula (XII). The amount of the inert solvent is usually from 5 to1,000 parts by weight, preferably from 10 to 100 parts by weight, perpart by weight of the compound of the formula (XII). The reactiontemperature for the above Wittig Reaction is usually from -150° C. to+200° C., preferably from -80° C. to -100° C.

Difluoroprostacyclins of the formula (IV) ##STR10##

In the formula (IV), A, Q, R¹ and R³ are as defined above.

The difluoroprostacyclins of the formula (IV) prepared by the abovedescribed introduction of the α-chain moiety and introduction of theω-chain moiety, have protecting groups. Accordingly, it is usuallynecessary to remove the protecting groups in order to obtain compoundshaving physiological activities. Further, when Q does not have a desiredfunctional group in the final product, conversion to such a functionalgroup is required. The product can be converted to a compound in whichthe structure of Q is different, by subjecting the product to a reactionto remove protecting groups, a reaction to convert it to a carboxylicacid by oxidation, a reaction to remove protecting groups for a hydroxylgroups, hydrolysis of an ester, or a reaction to form a salt of acarboxylic acid. For example, when Q is -B-Z wherein Z is an analogousgroup to a carboxyl group, a formyl group, a protected formyl group, ahydroxyl group or a protected hydroxyl group, Z can be converted to acarboxyl group by a usual reaction for conversion for a functionalgroup, such as a reaction to remove a protecting group, hydrolysis or anoxidation reaction. Usually, protecting groups as R¹ and R³ are removed,and Z having a polar group other than a carboxyl group, is converted toa carboxyl group. Such an reaction to remove the protective group andconversion to a carboxyl group may be conducted simultaneously orsequentially i.e. one after the other.

Accordingly, preferred difluoroprostacyclins of the formula (IV) arecompounds wherein each of R¹ and R³ is a hydrogen atom, and Q is-B-COOH, their lower alkanol esters, and their pharmaceuticallyacceptable salts. The lower alkanol esters and their salts may be thesame as will be described hereinafter with respect todifluoroprostacyclins of the formula (V).

The difluoroprostacyclin of the formula (IV) has an asymmetric carbon inits structure and thus has various stereoisomers and optical isomers.The compounds of the present invention include, all of suchstereoisomers, optical isomers and their mixtures. The same is true withrespect to the difluoroprotacyclin of the formula (V).

Difluoroprostacyclins of the formula (V)

Among difluoroprostacyclins of the formula (IV), more preferredcompounds ace difluoroprostacyclins of the following formula (V), theirlower alkanol esters, or their pharmaceutically acceptable salts.##STR11##

In the formula (V), A and R are as defined above. The lower alkanolester of the difluoroprostacyclin of the formula (V) is an ester formedby the reaction of a carboxyl group of the α-chain of thedifluoroprostacyclin of the formula (V) with a lower alkanol. As thelower alkanol, a lower alkanol having not more than four carbon atoms ispreferred. Particularly preferred is a C₁₋₂ lower alkanol. Specificlower alkanols include, for example, methanol, ethanol, n-propanol,i-propanol, n-butanol, i-butanol, and t-butanol. Such a lower alkanolester of the difluoroprostacyclin is useful as an intermediate for thesynthesis of the corresponding difluoroprostacyclin, and it is believedto be useful also as a prodrug showing physiological activities, whenconverted to the corresponding difluoroprostacyclin in vivo.

The pharmaceutically acceptable salt of the difluoroprostacyclin of theformula (V) is a salt of the carboxyl group moiety with a basicsubstance and a compound having the hydrogen atom of a carboxyl groupsubstituted by a cation. As such a cation, an ammonium cation such asNH⁴⁺ tetramethyl ammonium, monomethyl ammonium, dimethyl ammonium,trimethyl ammonium, benzyl ammonium, penetyl ammonium, morpholiumcation, monoethanol ammonium, triscation or piperidinium cation, analkali metal cation such as Na+ or K+, a metal cation other than thealkali metal such as 1/2 Ca²⁺, 1/2 Mg²⁺, 1/2 Zn²⁺ or 1/3 Al³⁺ may forexample, be mentioned Preferred cations are sodium ion and potassiumion.

Physical properties of difluoroprostacyclins

The present inventors have found that the difluoroprostacyclins of theformulas (IV) and (V) of the present invention have surprisingly goodstability. As mentioned above, the half-life of natural typeprostacyclin is about 10 minutes. Further, the half-life of10,10-difluoro-13,14-dehydroprostacyclin disclosed in theabove-mentioned Japanese International Patent Publication No.501319/1981 is reported to be about 24 hours. The life time of the moststable compound (the one having a m-phenylene group in the α-chain) as asynthetic prostacyclin having the same vinyl ether structure, isreported to be about nine days. Whereas, the difluoroprostacyclins ofthe present invention have a half-life of at least about three months.

According to the study by the present inventors, the physiologicalactivities of the difluoroprostacyclins of the present invention tend tobe influenced by the type of the ω-chain. As mentioned above, in thegeneral formulas (IV) and (V), compounds wherein A is a vinylene grouphave relatively high physiological activities. Among them, compoundswherein R is a branched chain hydrocarbon group have high physiologicalactivities. Such compounds with particularly high physiologicalactivities have substantially equal or higher physiological activitiesas compared with natural type prostacyclin.

7,7-difluoro-13,14-dehydroprostacyclin disclosed in the above-mentionedJapanese International Patent Publication No. 501319/1981 is a compoundof of the formula (V) wherein A is an ethynylene, and R is a n-pentylgroup. The present inventors have synthesized this compound by a methodas described hereinafter and measured its chemical stability and itsphysiological activities. As a result, it has been found that thiscompound has chemical stability substantially equal to other compounds(i.e. very high stability as compared with natural type prostacyclin,but its physiological activities are inadequate and substantially lowerthan natural type prostacyclin.

The difluoroprostacyclins of the formula (IV), the difluoroprostacyclinsof the formula (V), their lower alkanol esters, or theirpharmaceutically acceptable salts, of the present invention, are usefulas active ingredients for preventive or therapeutic agents for diseasesof circulatory organs. They are believed to be particularly useful astherapeutic agents for arteriosclerotic diseases, such as anginapectoris, cardiac infarction, cerebral infarction and hypertension,neuropathy due to diabetes, peripheral blood circulatory disorder, orscleroderma. The difluoroprostacyclins of the present invention may beadministered by injection. Otherwise, by utilizing their high stability,oral administration or other methods of administration may be employed.

Now, the present invention will be described in further detail withreference to Examples. However, the present invention is by no meansrestricted to such specific Examples.

The scheme of Examples will be shown below. Examples 1 to 39 arepreparation Examples for compounds, wherein compounds were identified bynumbers. Among them, Examples 10 to 29 are Examples in which variousω-chains were introduced to Compound 9 prepared in Example 7. Examples38 to 39 are Examples in which 7,7-difluoro-13,14-dehydroprostacyclindisclosed in the above-mentioned Japanese International PatentPublication No. 501319/1981 is prepared in accordance with the processof the present invention. Examples 40 and 41 are Examples in which thestability and the physiological activities of the synthesized compoundswere measured. ##STR12##

EXAMPLE 1 Preparation of(1S,5R,6R,7R)-2-oxa-4-fluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methyl-bicyclo[3.3.0]octan-3-one(Compound No. 2)

To a tetrahydrofuran (hereinafter referred to simply as THF) (90 ml)solution of hexamethyldisilazane (6.84 ml), 19.1 ml of n-butyl lithium(a 1.56 M hexane solution) was added at -78° C., and the mixture wasstirred for 30 minutes to obtain a lithium hexamethyldisilazidesolution. To this solution, a THF (20 ml) solution of 10 g of(1S,5R,6R,7R)-2-oxa-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methyl-bicyclo[3.3.0]octan-3-one(Compound 1) was dropwise added at -78° C., and the mixture was stirredfor 60 minutes. Then, a THF (40 ml) solution of 9.37 g ofN-fluorobenzenesulfonimide was added thereto at -78° C. The mixture wasstirred at -78° C. for 60 minutes, then stirred at room temperature for30 minutes. Then, it was poured into a saturated sodium hydrogencarbonate aqueous solution, and the mixture was extracted with ethylacetate. The extract was purified by silica gel column chromatography(ethyl acetate:hexane=1:8 to 1:4) to obtain 9.46 g of theabove-identified compound. ¹ H-NMR (CDCl₃) δ (ppm): 0.05 (m, 6H), 0.88(m, 9H), 1.4-1.8 (m, 6H), 2.0-3.1 (m, 4H), 3.4-5.3 (m, 8H).

¹⁹ F-NMR(CDCl₃, ppm): -179(m).

EXAMPLE 2 Preparation of(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methylbicyclo[3.3.01octan-3-one(Compound 3)

To 136 mg (1 mmol) of anhydrous zinc chloride, a THF (3 ml) solution of194 mg of(1S,5R,6R,7R)-2-oxa-4-fluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methyl-bicyclo[3.3.0]octan-3-one(Compound 2) prepared in Example 1, was added at room temperature, andthe mixture was cooled to -78° C. Then, 1 ml of lithium diisopropylamide(a 1M THF solution) was added thereto, and the mixture was stirred for20 minutes. To this solution, 236 mg (0.75 mmol) ofN-fluorobenzenesulfonimide was added at -78° C., and the mixture wasstirred for 1.5 hours. The reaction solution was poured into a saturatedsodium hydrogen carbonate aqueous solution, and the mixture wasextracted with ethyl acetate. The extract was purified by silica gelcolumn chromatography to obtain 126 mg of the above-identified compound.

¹ H-NMR(CDCl₃) δ (ppm) :0.06(m,6H), 0.89 (m, 9H), 1.2-2.3(m, 8H),2.6-2.7 (m, 1H), 3.09 (m, 1H), 3.4-3.9 (m, 4H), 4.23(m, 1H), 4.64 (m,1H), 5.12 (m, 1H).

¹⁹ F-NMR (CDCl₃, ppm): -94 (m), -115 (m).

Mass spectrum: 406(M⁺).

EXAMPLE 3 Preparation of(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methylbicyclo[3.3.0]octan-3-one(Compound 3).

To 185 mg (1.5 mmol) of anhydrous manganese bromide, dry tetrahydrofuran(3 ml) was added. Then, a dry THF solution (3 ml) of 473 mg (1.5 mmol)of N-fluorobenzenesulfonimide was added thereto at room temperature, andthe mixture was stirred for one hour. Then, a THF (3 ml) solution of 185mg of(1S,5R,6R,7R)-2-oxa-7-(2-tetrahydropyrcanyloxy)-6-(t-butyldimethylsiloxy)methyl-bicyclo[3.3.0]octan-3-one(Compound 1) was added thereto at -78° C., and 4 ml of potassiumhexamethyldisilazide (a 0.5M toluene solution) was added thereto. Themixture was stirred at -78° C. for one hour and at 0° C. for one hour.The reaction solution was poured into a saturated sodium hydrogencarbonate aqueous solution, and the mixture was extracted with ethylacetate. The extract was purified by silica gel column chromatography toobtain 110 mg of the above-identified compound.

¹ H-NMR (CDCl₃) δ (ppm) :0.06 (m, 6H), 0.89 (m, 9H), 1.2-2.3 (m, 8H),2.6-2.7 (m, 1H), 3.09 (m, 1H), 3.4-3.9 (m, 4H), 4.23 (m, 1H), 4.64 (m,1H), 5.12 (m, 1H).

¹⁹ F-NMR (CDCl₃, ppm): -94 (m), -115 (m).

Mass spectrum: 406 (M⁺).

Except that the type of the metal compound was changed, preparation ofthe above-identified compound was conducted using the same materialsunder the same conditions as described above. The type of the metalcompound used and the yield of the above-identified compound are shownin Table 1. The abbreviations used in the Table for metal compoundreagents are as follows.

CpZrCl₂ : zirconocene dichloride

Zn(OTf)₂ : zinc trifluoromethanesulfonate

                  TABLE 1                                                         ______________________________________                                        No.        Metal compound                                                                             Yield (%)                                             ______________________________________                                        1          (Nil)        Trace                                                 2          ZnCl.sub.2   28                                                    3          ZnI.sub.2    20                                                    4          Cp.sub.2 ZrCl.sub.2                                                                        52                                                    5          Zn(OTf).sub.2                                                                              25                                                    6          CeCl.sub.3   45                                                    ______________________________________                                    

EXAMPLE 4 Preparation of1-(4-iodobutyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (Compound 4)

This compound was prepared as follows, in the same manner as in themethod disclosed by E. J. Corey et al., Tetrahedron Lett., 24, 5571(1983). To a methylene chloride (20 ml) solution of 4.42 g of3-methyl-3-hydroxymethyloxetane, 5 ml of pyridine and 12.2 g of5-iodopentanoic acid chloride were added at 0° C., and the mixture wasstirred for two hours. The reaction mixture was poured into an aqueoussodium hydrogen carbonate solution, and the mixture was extracted withmethylene chloride. Then, the extract was purified by silica gel columnchromatography to obtain 13.0 g of the corresponding ester. To a drymethylene chloride (20 ml) solution of 6.24 g of this ester, 0.62 ml ofboron trifluoride etherate was added at -15° C., and the mixture wasstirred at -15° C. for 4 hours, at 0° C. for two hours and at roomtemperature for one hour. After adding 2.79 ml of triethylamine at 0°C., the reaction solution was concentrated and purified by silica gelcolumn chromatography to obtain 5.42 g of the above-identified compound.

¹ H-NMR (CDCl₃) δ (ppm): 0.80 (s, 3H), 1.5-1.9(m, 6H), 3.17 (t, j=7.2Hz, 2H), 3.89 (s,6H).

EXAMPLE 5 Preparation of(1S,5R,6R,7R)-2-oxa-3-(4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octanyl)butylidene)-4,4-difluoro-6-(t-butyldimethylsiloxy)methyl-7-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octane(Compound 5)

A dry ethyl ether (5 ml) solution of 195 mg of1-(4-iodobutyl)-4-methlyl-2,6,7-trioxabicyclo[2.2.2]octane (Compound 4)prepared in Example 4, was cooled to -78° C., and 0.87 ml of t-butyllithium (a 1.48 M pentane solution) was added thereto. The mixture wasstirred at -78° C. for two hours. An ethyl ether solution (2 ml) of 209mg of(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methylbicyclo[3.3.0]octan-3-one(Compound 3) was added thereto at -78° C., and the mixture was stirredat -78° C. for one hour and at -60° C. for one hour. The reactionsolution was poured into an aqueous sodium hydrogen carbonate solution,and the mixture was extracted with ethyl acetate. The extract solutionwas washed with a saturated sodium chloride aqueous solution and thenconcentrated under reduced pressure. To the residue, 2 ml of methylenechloride was added, and after adding 0.53 ml of triethylamine and 0.14ml of methanesulfonyl chloride at 0° C., the mixture was stirred at roomtemperature for 1.5 hours. The mixture was poured into an aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The extract solution was concentrated under reduced pressureand purified by silica gel column chromatography (ethylacetate:hexane=1:30 to 1:10) to obtain 263 mg of the above-identifiedcompound.

¹ H-NMR(CDCl₃) δ (ppm) :0.05(m, 6H), 0.8-2.9(m, 28H), 3.4-4.7 (m, 14H).

¹⁹ F-NMR (CDCl₃, ppm): -83 (m), -115 (m).

EXAMPLE 6 Preparation of methyl 5-[(1S,5R,6R,7R)-2-oxa-44-difluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methyl-bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 8)

To a 1,2-dimethoxyethane (5 ml) solution of 263 mg of(1S,5R,6R,7R)-2-oxa-3-{4-(4-methyl-2,6,7trioxabicyclo[2.2.2]octanyl)butylidene{-4,4-difluoro-6-(t-butyldimethylsiloxy)methyl-7-(2tetrahydropyranyloxy)bicyclo[3.3.0]octane(Compound 5) prepared in Example 5, 0.5 ml of a 10% sodium hydrogensulfate aqueous solution was added at 0° C., and the mixture was stirredfor 30 minutes. The mixture was poured into an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract solution was concentrated under reduced pressure. To theresidue, 5 ml of methanol and 136 mg of potassium carbonate were added,and the mixture was stirred at room temperature for two hours. Themixture was poured into an aqueous sodium hydrogen carbonate solution,and the mixture was extracted with ethyl acetate-hexane (1:1). Theextract solution was concentrated under reduced pressure and purified bysilica gel column chromatography (ethyl acetate:hexane=1:30 to 1:10) toobtain 191 mg of the above-identified compound.

¹ H-NMR(CDCl₃) δ (ppm):0.05(m, 6H), 0.8-2.9 (m, 25H),3.67(s, 3H),3.4-4.7 (m, 8H).

¹⁹ F-NMR (CDCl₃, ppm): -83 (m), -115 (m).

EXAMPLE 7 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxymethylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9 )

To a THF (10 ml) solution of 340 mg of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 8) prepared in Example 6, 780 μl of tetrabutyl ammoniumfluoride (a 1M THF solution) was added at 0° C. The mixture was stirredat room temperature for two hours. Then, the solvent was removed, andthe residue was purified by silica gel column chromatography (methylenechloride:methanol=20:1) to obtain 150 mg of the above-identifiedcompound.

¹ H-NMR (CDCl₃) δ (ppm): 1.3-2.9 (m, 16H), 3.67 (s, 3H), 3.4-4.7 (m,8H).

¹⁹ F-NMR (CDCl₃, ppm): -83 (m), -115 (m).

EXAMPLE 8 Preparation of(1S,5R,6R,7R)-2-oxa-3-(1,4-pentadienylidene)-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methylbicyclo[3.3.0]octane(Compound 6).

To an ethyl ether (10 ml) solution of 550 mg of(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methylbicyclo[3.3.0]octan-3-one(Compound 3), a Grignard solution prepared from 0.20 ml of5-bromo-1-pentene and 48 mg of magnesium in dry ethyl ether, was addedat -78° C. The mixture was stirred for one hour. The reaction solutionwas poured into a saturated sodium hydrogen carbonate aqueous solution,and the mixture was extracted with ethyl acetate. The extract wasconcentrated under reduced pressure. Then, 10 ml of methylene chloride,0.70 ml of triethylamine and 0.195 ml of methanesulfonyl chloride wereadded thereto at 0° C. Then, the mixture was stirred at room temperaturefor 1.5 hours. The mixture was poured into an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate.The extract solution was concentrated under reduced pressure andpurified by silica gel column chromatography (ethyl acetate:hexane=1:30to 1:20) to obtain 0.22 g of the above-identified compound.

¹ H-NMR (CDCl₃) δ (ppm): 0.6-0.08 (m, 6H), 0.8-0.9 (m, 9H), 1.1-2.9 (m,14H), 3.4-5.8 (m, 11H).

¹⁹ F-NMR(CDCl₃, ppm): -83(m), -115(m).

EXAMPLE 9 Preparation of(1S,5R,6R,7R)-2-oxa-3-(5-triethylsiloxybentylidene)-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methylbicyclo[3.3.0]octane(Compound 7)

The above-identified compound was prepared in the same manner as inExample 5 using(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methyl-bicyclo[3.3.0]octan-3-one(Compound 3) and 5-iodopentanol triethylsilyl ether.

¹ H-NMR(CDCl₃) δ (ppm): 0.05(s, 6H), 0.5-1.0(m, 24H), 1.1-2.9 (m, 16H),3.4-4.7 (m, 9H).

¹⁹ F-NMR (CDCl₃, ppm): -83(m), -115 (m).

EXAMPLE 10 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S,5S)-3-hydroxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 10)

To a benzene (3 ml) solution of 150 mg of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxymethylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9) prepared in Example 7, 29 μl of pyridine, 30 μl of dimethylsulfoxide, 4 μl of trifluoroacetic acid and 217 mg ofdicyclohexylcarbodiimide were added, and the mixture was stirred at roomtemperature for one hour. Insoluble materials were filtered off, and thefiltrate was washed with water and concentrated to obtain a crudeproduct of the corresponding aldehyde.

To a 1,2-dimethoxyethane (5 ml) solution of 235 mg of dimethyl(4S)-4-methyl-2-oxooctanyl phosphonate, 37 mg of sodium hydride wasadded, and the mixture was stirred for 10 minutes. To this solution, theabove-mentioned 1,2-dimethoxyethane (3 ml) solution of the crude productof the aldehyde was added at 0° C., and the mixture was stirred at roomtemperature for 30 minutes. Then, the mixture was poured into an aqueoussodium chloride solution, and the mixture was extracted with ethylacetate. The extract was concentrated by drying and purified by silicagel column chromatography (ethyl acetate:hexane=1:4 to 1:1) to obtain120 mg of the corresponding nonene. To this methanol (5 ml) solution,102 mg of cerium chloride heptahydrate and 15 mg of sodium borohydridewere added at -40° C., and the mixture was stirred at -40° C. for 10minutes and at 0° C. for 30 minutes. Then, the mixture was poured into asaturated sodium hydrogen carbonate aqueous solution, and the mixturewas extracted with ethyl acetate.

After concentration, the residue was dissolved in methanol (5 ml), and 5mg of p-toluenesulfonic acid monohydrate was added thereto at 0° C. Themixture was stirred at room temperature for one hour. Methanol wasdistilled off, and then a saturated sodium hydrogen carbonate aqueoussolution and ethyl acetate were added. The mixture was extracted. Theextract solution was concentrated by drying and purified by silica gelcolumn chromatography (methylene chloride:acetone=1:2) to obtain 39 mgof the above-identified compound. ¹ H-NMR(CDCl₃) δ (ppm): 0.8-3.0 (m,25H), 3.4-5.2 (m, 6H), 6.2-6.8 (m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -179 (m).

EXAMPLE 11 Preparation of sodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S,5S)-3-hydroxy-5-methyl-E-1nonenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 11)

To an ethanol (8 ml) solution of 139 mg of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S,5S)-3-hydroxy-5-methyl-E-1-nonenyl}bicyclo[3.3.01octan-3ylidene]pentanoate(Compound 10) prepared in Example 10, 3.39 ml of 0.1N sodium hydroxidewas added, and the mixture was stirred at room temperature for 14 hours.The mixture was concentrated under reduced pressure to obtain 125 mg ofthe above-identified compound.

¹ H-NMR (D₂ O) δ (ppm): 0.8-2.9 (m, 25H), 3.7-4.3 (m, 2H), 4.5-5.0 (m,2H), 5.5-5.7 (m, 2H).

¹⁹ F-NMR (D₂ O, ppm): -84 (dd, J=17,250 Hz), -117 (d, J=250 Hz).

EXAMPLE 12 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-cyclopentyl-3-hydroxy-E-1-propenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 12)

The above-identified compound was prepared by the same method as inExample 10 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxymethylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9) prepared in Example 7 and dimethyl 2-oxo-2cyclopentylethylphosphonate.

¹ H-NMR (CDCl₃) δ (ppm): 1.1-2.7 (m, 19H), 3.67 (s, 3H), 3.8-4.3 (m,2H), 4.7-4.9 (m, 2H), 5.4-5.7 (m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -84 (dd, J: 17,250 Hz), -117 (d, J=250 Hz).

Mass spectrum: 401 (M⁺ +1).

EXAMPLE 13 Preparation of sodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-cyclopentyl-3-hydroxy-E-1-propenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 13)

The above-identified compound was prepared by the same method as inExample 11 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-cyclopentyl-3-hydroxy-E-1-propenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 12) prepared in Example 12.

¹ H-NMR (D₂ O) δ (ppm): 1.0-2.9 (m, 19H), 3.7-4.3 (m, 2H), 4.5-5.0 (m,2H), 5.4-5.7 (m, 2H).

¹⁹ F-NMR (D₂ O, ppm): -84 (dd, J=17,250 Hz), -117 (d, J=250 Hz).

EXAMPLE 14 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S,4RS)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 14)

The above-identified compound was prepared by the same method as inExample 10 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxymethylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9) prepared in Example 7 and dimethyl 3-methyl-2-oxo-5-octynylphosphonate.

¹ H-NMR (CDCl₃) δ (ppm): 0.8-2.8 (m, 21H), 3.67 (s, 3H), 3.9-4.3 (m, 2H4.7-4.9 (m, 2H), 5.4-5.7 (m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -8.1 (m), -117 (m).

Mass spectrum: 427 (M⁺ +1).

EXAMPLE 15 Preparation of sodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S,4RS)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 15)

The above-identified compound was prepared by the same method as inExample 11 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S,4RS)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 14) prepared in Example 14.

¹ H-NMR (D₂ O) δ (ppm): 0.7-2.8 (m, 21H), 3.7-4.3 (m, 2H), 4.5-5.0 (m,2H), 5.3-5.7 (m, 2H).

¹⁹ F-NMR (D₂ O, ppm): -84 (m), -117 (m).

EXAMPLE 16 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S,4S)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 16)

The above-identified compound was prepared by the same method as inExample 10 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxymethylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9) prepared in Example 7 and dimethyl(3S)-3-methyl-2-oxo-5-octynyl phosphonate.

¹ H-NMR (CDCl₃) δ (ppm): 0.8-2.8 (m, 21H), 3.67 (s, 3H), 3.9-4.3 (m,2H), 4.7-4.9 (m, 2H), 5.4-5.7 (m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -84 (dd, j=17,249 Hz), -117 (d, J=250 Hz).

Mass spectrum; 427 (M⁺ +1).

EXAMPLE 17 Preparation of sodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S,4S)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 17)

The above-identified compound was prepared by the same method as inExample 11 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S,4S)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3ylidene]pentanoate(Compound 16) prepared in Example 16.

¹ H-NMR (D₂ O) δ (ppm): 0.7-2.8(m, 21H), 3.7-4.3 (m, 2H), 4.5-5.0 (m,2H), 5.3-5.7 (m, 2H).

¹⁹ F-NMR (D₂ O, ppm): -84 (dd, J=17,250 Hz), -117 (d, J=250 Hz).

EXAMPLE 18 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-hydroxy-E-1octenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 18)

The above-identified compound was prepared by the same method as inExample 10 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxy-methylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9) prepared in Example 7 and dimethyl 2-oxo-heptynylphosphonate.

¹ H-NMR (CDCl₃) δ (ppm): 0.9-2.7 (m, 21H), 3.67 (s, 3H), 3.9-4.3 (m,2H), 4.7-4.9 (m, 2H), 5.5-5.7 (m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -84 (dd, J=16,249 Hz), -117 (d, J=249Hz).

Mass spectrum: 403 (M⁺ +1).

EXAMPLE 19 Preparation of sodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-hydroxy-E-1-octenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 19)

The above-identified compound was prepared by the same method as inExample 11 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-hydroxy-E-1-octenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 18) prepared in Example 18.

¹ H-NMR (D₂ O) δ (ppm): 0.8-2.9 (m, 21H), 3.7-4.3 (m, 2H), 4.5-5.0 (m,2H), 5.4-4.7 (m, 2H).

¹⁹ F-NMR (D₂ O, ppm): -84 (dd, J=17,250 Hz), -117 (d, J=250 Hz).

EXAMPLE 20 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-hydroxy-4-(3-methylphenyl)-E-1-butenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 20)

The above-identified compound was prepared by the same method as inExample 10 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxymethylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9) prepared in Example 7 and dimethyl2-oxo-3-(3-methylphenyl)propyl phosphonate.

¹ H-NMR (CDCl₃) δ (ppm): 1.4-2.9(m, 12H), 2.33 (m, 3H), 3.67 (S, 3H),3.89 (m, 1H), 4.32 (m, 1H), 4.7-4.9(m, 2H), 5.5-5.8(m, 2H), 7.0-7.2 (m,4H) ¹⁹ F-NMR (CDCl₃, ppm): -84 (dd, J=12,253 Hz), -116 (d, J=253 Hz)

EXAMPLE 21 Preparation ofsodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-hydroxy-4-(3-methylphenyl)-E-1-butenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 21).

The above-identified compound was prepared by the same method as inExample 11 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-hydroxy-4-(3-methylphenyl)-E-1-butenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 20) prepared in Example 20.

¹ H-NMR (D₂ O) δ (ppm): 1.4-2.9 (m, 15H), 3.8-4.4 (m, 2H), 4.7-4.9 (m,2H), 5.5-5.8 (m, 2H), 7.0-7.2 (m, 4H)

¹⁹ F-NMR (D₂ O, ppm): -84 (dd, J=12,253 Hz), -116 (d, J=253 Hz)

EXAMPLE 22 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R,5S)-3-hydroxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 22)

The above-identified compound was prepared by the same method as inExample 10 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxymethylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9) prepared in Example 7 and dimethyl(4S)-4-methyl-2-oxooctanyl phosphonate and isolated by means of silicagel column chromatography (hexane:ethyl acetate=1:2) as an isomer havinga polarity lower than the above-identified compound in Example 10, toobtain 30 mg of the above-identified compound.

¹ H-NMR (CDCl₃) δ (ppm): 0.8-2.7 (m, 25H), 3.68 (s, 3H), 3.9-4.0 (m,1H), 4.1-4.2 (m, 1H), 4.8-4.9 (m, 2H), 5.6-5.7 (m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -84 (dd, J=17, 254 Hz), -116 (d, J=254 Hz)

EXAMPLE 23 Preparation of sodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R,5S)-3-hydroxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 23)

The above-identified compound was prepared by the same method as inExample 11 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R,5S)-3-hydroxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 22) prepared in Example 22.

¹ H-NMR (D₂ O) δ (ppm): 0.8-2.8 (m, 25H), 3.9-4.2 (m, 2H), 4.5-5.0 (m,2H), 5.5-5.6 (m, 2H).

¹⁹ F-NMR (D₂ O, ppm): -84 (dd, J=17,248 Hz), -117 (d, J=248Hz)

EXAMPLE 24 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R,4RS)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 24)

The above-identified compound was prepared by the same method as inExample 10 using methyl5-[(1S,5R,6R,7R)-2-oxa-1,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxymethylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9) prepared in Example 7 and dimethyl(3RS)-3-methyl-2-oxo-5-octynyl phosphonate and isolated by means ofsilica gel column chromatography (hexane:ethyl acetate=1:2) as an isomerhaving a polarity lower than the above-identified compound in Example14.

¹ H-NMR (CDCl₃) δ (ppm): 0.9-2.8 (m, 21H), 3.68 (s, 3H), 3.9-4.3 (m, 2H), 4.8-4.9 (m, 2H), 5.6-5.8 (m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -83-84 (m), -116--117 (m).

EXAMPLE 25 Preparation of sodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R,4RS)-3-hydroxy-4-methyl-E-1-none-6-ynyl}bicyclo[3.3.0]octan-3-ylidenelpentanoate(Compound 25)

The above-identified compound was prepared by the same method as inExample 11 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R,4RS)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 24) prepared in Example 24.

¹ H-NMR (D₂ O) δ (ppm): 0.8-2.9 (m, 2H), 3.9-4.1 (m, 2H), 4.5-5.0 (m,2H), 5.5-5.6 (m, 2H)

¹⁹ F-NMR (D₂ O, ppm): -83--84 (m), -116--117 (m).

EXAMPLE 26 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-}[(3R,4S)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 26)

The above-identified compound was prepared by the same method as inExample 10 using methyl5-[(1S,5R,6R,7R)-2-oxa-1,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxymethylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9) prepared 9 in Example 7 and dimethyl(3S)-3-methyl-2-oxo-5-octynyl phosphonate and isolated by means ofsilica gel column chromatography (hexane:ethyl acetate=1:2) as an isomerhaving a polarity lower than the above-identified compound in Example16.

¹ H-NMR (CDCl₃) δ (ppm): 1.0-2.7 (m, 21H), 3.68 (s, 3H), 3.9-4.3 (m, 2H), 4.8-4.9 (m, 2H), 5.6 (m, 2H)

¹⁹ F-NMR )CDCl₃, ppm): -84 (dd, J=17, 254 Hz), -116 (d, J=254 Hz).

EXAMPLE 27 Preparation ofsodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R,4S)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 27)

The above-identified compound was prepared by the same method as inExample 11 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R,4S)-3-hydroxy-4-methyl-E-1-nonen-6-ynyl}bicyclo[3.3.0]octan-3ylidene]pentanoate(Compound 26) prepared in Example 26.

¹ H-NMR (D₂ O) δ (ppm): 0.8-2.9 (m, 2H), 3.9-4.1 (m, 2H), 4.5-5.0 (m,2H), 5.5-5.6 (m, 2H)

¹⁹ F-NMR (D₂ O, ppm): -84 (dd, J=17, 248 Hz), -117 (d, J=248 Hz)

EXAMPLE 28 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R)-3-hydroxy-4-(3-methylphenyl)-E-1-butenyl)bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 28)

The above-identified compound was prepared in the same manner as inExample 10 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-hydroxymethylbicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 9) prepared in Example 7 and dimethyl2-oxo-3-(2-methylphenyl)propyl phosphonate and isolated by means ofsilica gel column chromatography (methylene chloride:acetone=2:1) as anisomer having a polarity lower than the above-identified compound inExample 20.

¹ H-NMR (CDCl₃) δ (ppm): 1.7-2.9 (m, 12H), 2.32 (m, 3H), 3.66 (S, 3H),3.80 (m, 1H), 4.33 (m, 1H), 4.7-4.9 (m, 2H), 5.4-5.8 (m, 2H), 7.0-7.2(m, 4H)

¹⁹ F-NMR (CDCl₃, ppm): -84(dd, J=12,253 Hz), -116 (d, J=253 Hz)

EXAMPLE 29 Preparation of sodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R)-3-hydroxy-4-(3-methylphenyl)-E-1-butenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 29)

The above-identified compound was prepared by the same method as inExample 11 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3R)-3-hydroxy-4-(3-methylphenyl)-E-1-butenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 28) prepared in Example 28.

¹ H-NMR (D₂ O) δ (ppm): 1.6-3.0 (m, 15H), 3.8-4.4 (m, 2H), 4.7-4.9 (m,2H), 5.4-5.8 (m, 2H), 7.0-7.2 (m, 4H)

¹⁹ F-NMR (D₂ O, ppm): -84 (dd, J=12,253 Hz), -116 (d, J=253 Hz)

EXAMPLE 30 Preparation of(1S,5R,6R,7R)-2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S,5S)-3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl)bicyclo[3.3.0]octan-3-one(Compound 33)

To a THF (1 ml) solution of hexamethyldisilazane (51 μl, 0.242 mmol),0.14 ml of n-butyl lithium (1.56 M, hexane solution) was added at -78°C., followed by stirring for 30 minutes to obtain a lithiumhexamethyldisilazide solution. To this solution, a THF solution (2 ml)of 105 mg of(1S,5R,6R,7R)-2-oxa-7-t-butyldimethylsiloxy-6-{(3S,5S)-3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-one(Compound 32) was dropwise added at -78° C., and the mixture was stirredfor 30 minutes. Then, 76.2 mg of N-fluorobenzenesulfonimide was addedthereto at -78° C. The mixture was stirred at -78° C. for 15 minutes, at0° C. for 30 minutes and at room temperature for 30 minutes and thenpoured into a saturated ammonium chloride aqueous solution, and themixture was extracted with ethyl acetate. The extract was purified bysilica gel column chromatography (ethyl acetate:hexane=1:30 to 1:10) toobtain 40 mg of the above-identified compound.

¹ H-NMR (CDCl₃) δ (ppm): 0.04 (m, 12H), 0.86 (m, 24H), 1.0-4.2 (m, 15H),4.9-5.7 (m, 4H).

¹⁹ F-NMR (CDCl₃, ppm): -177 (dd, J=30.2, 52.7 Hz), -203 (d, J=48.8 Hz).

Mass spectrum: 542(M⁺)

EXAMPLE 31 Preparation of(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S,5S)-3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-one(Compound 34)

To a THF (14 ml) solution of diisopropylamine (1.23 ml, 0.9 mmol), 4.88ml of n-butyl lithium (1.66 M, hexane solution) was added at -78l ° C.,followed by stirring for 30 minutes to obtain a lithium diisopropylamidesolution. In a separate container, 1.47 g (10.8 mmol) of anhydrous zincchloride was taken, and a THF solution (20 ml) of 3.57 g (6.76 mmol) of(1S,5R,6R,7R)-2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S)-3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-one(Compound 33) prepared in Example 30 was added thereto. This solutionwas cooled to -78° C., and the above-mentioned lithium diisopropylamidesolution was dropwise added thereto at -78° C. The mixture was stirredfor 20 minutes. Then, 2.56 g (8.1 mmol) of N-fluorobenzenesulfonimidewas added thereto at -78° C. The mixture was stirred at -78° C. for 30minutes and at room temperature for 30 minutes, and then poured into asaturated sodium hydrogen carbonate aqueous solution. The mixture wasextracted with ethyl acetate. The extract was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:30 to 1:10) to obtain 2.90g of the above-identified compound.

¹ H-NMR (CDCl₃) δ (ppm): 0.04 (m, 12H), 0.84-0.88 (m, 24H), 1.0-1.5 (m,9H), 2.1-2.2 (m, 2H), 2.9-3.1 (m, 2H), 4.0-4.2 (m, 2H), 5.15 (m,1H),5.36 (dd, J=7.7, 15.3 Hz, 1H) 5.54 (dd, J=6.3, 15.3 Hz, 1H).

¹⁹ F-NMR (CDCl₃, ppm): -92 (dd, J=26, 282Hz), -114 (d, J=282 Hz).

Mass spectrum: 560 (M⁺)

EXAMPLE 32 Preparation of(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S,5S)-3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-one(Compound 34)

513 mg of the above-identified compound was obtained in the same manneras in Example 3 using 854 mg (1.62 mmol) of(1S,5R,6R,7R)-2-oxa-7-t-butyldimethylsiloxy-6-{(3S,5S)-3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-one(Compound 32).

¹ H-NMR (CDCl₃) δ (ppm): 0.04 (m, 12H), 0.84-0.88 (m, 24H), 1.0-1.5 (m,9H), 2.1-2.2 (m, 2H), 2.9-3.1 (m, 2H), 4.0-4.2 (m, 2H), 5.15 (m, 1H),5.36 (dd, J=7.7, 15.3 Hz, 1H), 5.54 (dd, J=6.3, 15.3Hz, 1H).

¹⁹ F-NMR (CDCl₃, ppm): -92 (dd, J=26,282Hz), -114 (d, J=282Hz).

EXAMPLE 33 Preparation of(1S,5R,6R,7R)-2-oxa-3-{4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octanyl)butylidene}-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S,5S)-3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octane(Compound 35)

A dry ethyl ether (30 ml) solution of 1.13 g of1-(4-iodobutyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (Compound 4)was cooled to -78° C., and 5.07 ml of t-butyl lithium (1.48M, pentanesolution) was added thereto. The mixture was stirred at -78° C. for twohours. To this solution, an ethyl ether solution (10 ml) of 1.75 g of(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S,5S)-3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-one(Compound 34) was added at -78° C. The mixture was stirred -78° C. forone hour and at -60° C. for one hour. The mixture was poured into asodium hydrogen carbonate aqueous solution, and the mixture wasextracted with ethyl acetate. The extract solution was washed with asaturated sodium chloride aqueous solution and then concentrated underreduced pressure. To the residue, 10 ml of methylene chloride was added,and 2.6 ml of triethylamine and 0.72 ml of methanesulfonyl chloride wereadded at 0° C. Then, the mixture was stirred at room temperature for 1.5hours. The mixture was poured into a sodium hydrogen carbonate aqueoussolution, and the mixture was extracted with ethyl acetate. The extractsolution was concentrated under reduced pressure and then purified bysilica gel column chromatography (ethyl acetate:hexane=1:30 to 1:10) toobtain 1.83 g of the above-identified compound.

¹ H-NMR (CDCl₃) δ (ppm): 0.02-0.05 (m, 12H), 0.80-0.89 (m, 27H),1.2-2.5(m, 19H), 3.84(m, 1H), 3.88 (s, 6H), 4.13 (m, 1H), 4.7-4.9 (m,2H), 5.53 (m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -83 (d, J: 251 Hz), -115 (d, J=250 Hz).

EXAMPLE 34 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S,5S)-3-t-butyldimethylsiloxy-5-methyl-E-1nonenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 36)

To a 1,2-dimethoxyethane (25 ml) solution of 1.83 g of(1S,5R,6R,7R)-2-oxa-3-{4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octanyl)butylidene}-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S,5S)-3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octane(Compound 35) prepared in Example 33, 2.5 ml of a 10% sodium hydrogensulfate aqueous solution was added at 0° C., and the mixture was stirredfor 30 minutes. The mixture was poured into a sodium hydrogen carbonateaqueous solution, and the mixture was extracted with ethyl acetate. Theextract solution was concentrated under reduced pressure. To theresidue, 25 ml of methanol and 680 mg of potassium carbonate were added,and the mixture was stirred at room temperature for two hours. Themixture was poured into an aqueous sodium hydrogen carbonate solution,and the mixture was extracted with ethyl acetate-hexane (1:1). Theextract solution was concentrated under reduced pressure and purified bysilica gel column chromatography (ethyl acetate:hexane=1:30 to 1:10) toobtain 981 mg of the above-identified compound.

¹ H-NMR (CDCl₃) δ (ppm) :0.03-0.11 (m, 12H), 0. 85-0.89(m, 24H),1.1-2.6(m, 19H), 3.67 (s, 3H), 3.8-4.2 (m, 2H), 4.7-4.9 (m, 2H), 5.4-5.6(m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -83 (dd. J=14, 251 Hz), -115 (d, J=251 Hz).

Mass spectrum: 659 (M⁺ +1).

EXAMPLE 35 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S,5S)-3,hydroxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 10)

To a THF (15 ml) solution of 976 mg of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S,5S)-3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3ylidene]pentanoate(Compound 36) prepared in Example 34, 4.5 ml of tetrabutyl ammoniumfluoride (1 M, THF solution) was added, and the mixture was stirred atroom temperature for 18 hours. The reaction solution was concentratedunder reduced pressure and purified by silica gel column chromatographyto obtain 470 mg of the above-identified compound.

¹ H-NMR (CDCl₃) δ (ppm): 0.8-2.7 (m, 25H), 3.67 (s, 3H), 3.9-4.3 (m,2H), 4.7-4.9 (m, 2H), 5.5-5.7 (m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -84 (dd, J=17, 248 Hz), -117 (d, J=248 Hz).

Mass spectrum: 431 (M⁺ +1).

EXAMPLE 36 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-{(3S,5S)-3-(2-tetrahydropyranyloxy)-5-methyl-E-1nonenyl-}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 39)

To a dry THF (2 ml) solution of 180 mg of (4-carboxybutyl)triphenylphosphonium bromide, 0.81 ml of a 1.0 M sodium hexamethyldisilazide (THFsolution) was added, and the mixture was heated and refluxed for onehour. Then, a dry THF solution of 131 mg of(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-{(3S,5S)-3-(2-tetrahydropyranyloxy)-5-methyl-E-1-nonenyl}bicyclo[3.3.0]octan-3-one(Compound 38) was added thereto at room temperature, and the mixture wasstirred for 4 hours. The reaction solution was concentrated underreduced pressure, and an aqueous sodium hydrogen carbonate solution wasadded thereto. The mixture was extracted with ethyl acetate-hexane(1:1), and the extract solution was concentrated under reduced pressure.The residue was dissolved in benzene-methanol (4:1) (2.5 ml), and 1.3 mlof 10% trimethylsilyldiazomethane (hexane solution) was added thereto.The mixture was stirred at room temperature for 30 minutes. Acetic acidwas added thereto until nitrogen was no more generated. The mixture wasconcentrated under reduced pressure and purified by silica gel columnchromatography (ethyl acetate-hexane=1:7) to obtain 87 mg of theabove-identified compound.

¹ H-NMR (CDCl₃) δ (ppm):0.8-2.8 (m, 37H), 3.4-3.5 (m, 2H), 3.67 (s, 3H),3.8-4.3 (m, 4H), 4.6-4.9 (m, 4H), 5.3-5.7 (m, 2H).

¹⁹ F-NMR (CDCl₃, ppm): -83--84 (m), -115--117 (m).

Using the same materials as above, the above-identified compound wasprepared by changing the base. The base, the type of the base used andthe yield of the above-identified compound are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        No.        Base           Yield (%)                                           ______________________________________                                        1          NaN(SiMe.sub.3).sub.2                                                                        57                                                  2          NaNH.sub.2, (Me.sub.3 Si).sub.2 NH                                                           46                                                  3          n-BuLi         30                                                  4          t-BuOK         36                                                  5          KN(SiMe.sub.3).sub.2                                                                         56                                                  ______________________________________                                    

EXAMPLE 37 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methyl-bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 8)

The above-identified compound was prepared in the same manner as inExample 36 using(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-(2-tetrahydropyranyloxy)-6-(t-butyldimethylsiloxy)methyl-bicyclo[3.3.0]octan-3-one(Compound 3).

¹ H-NMR (CDCl₃) δ (ppm): 0.06(m, 6H), 0.89 (m, 9H), 1.2-2.7 (m, 15H),3.09 (m, 1H), 3.4-3.9 (m, 4H), 3.69 (s, 3H), 4.1 (m, 1H), 4.64 (m, 1H),4.7-4.8 (m, 2H).

¹⁹ F-NMR (CDCl, ppm): -84 (m), -117 (m)

EXAMPLE 38 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-hydroxy-1-octynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 30) Step 1 Preparation of(1S,5R,6R,7R)-2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S)-3-t-butyldimethylsiloxy-1-octynyl}-bicyclo[3.3.0]octan-3-one

(1S,5R,6R,7R)-2-oxa-7-hydroxy-6-{(3S)-3-hydroxy-1-octynyl}-bicyclo[3.3.0]octan-3-oneprepared by the method of Fried et al. (Tetrahedron Letters, 3899(1973)) was silylated by means of imidazole and t-butyldimethylsilylchloride in dimethylformamide to obtain(1S,5R,6R,7R)-2-oxa-7-t-butyldimethylsiloxy-6-{(3S)-3-t-butyldimethylsiloxy-1-octynyl}-bicyclo[3.3.0]octan-3-one.

To a THF (8 ml) solution of hexamethyldisilazane (615 μl), 1.66 ml ofn-butyl lithium (1.56M, hexane solution) was added at -78° C., followedby stirring for 30 minutes to obtain a lithium hexamethyldisilazidesolution. To this solution, a THF solution (10 ml) of 1.21 g of(1S,5R,6R,7R)-2-oxa-7-t-butyldimethylsiloxy-6-{(3S)-3-t-butyldimethylsiloxy-1-octynyl}-bicyclo[3.3.0]octan-3-onewas dropwise added at -78° C., and the mixture was stirred for 30minutes. Then, 930 mg of N-fluorobenzenesulfonimide was added thereto at-78° C. The mixture was stirred at -78° C. for 15 minutes, at 0° C. for30 minutes and at room temperature for 30 minutes, and then poured intoa saturated ammonium chloride aqueous solution. The mixture wasextracted with ethyl acetate. The extract was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:30 to 1:10) to obtain 643mg of the above-identified compound. ¹ H-NMR (CDCl₃) δ (ppm): 0.04 (m,12H), 0.88 (m, 21H), 1.0-5.4(m, 16H).

¹⁹ F-NMR (CDCl₃, ppm): -178 (dd, 30.1, 52.9 Hz).

Step 2 Preparation of(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S)-3-t-butyldimethylsiloxy-1-octynyl}-bicyclo[3.3.0]octan-3-one

To a THF (2 ml) solution of diisopropylamine (0.18 ml), 0.74 ml ofn-butyl lithium (1.66 M, hexane solution) was added at -78° C., followedby stirring for 30 minutes to obtain a lithium diisopropylamidesolution. In a separate container, 0.23 g of anhydrous zinc chloride wastaken, and a THF solution (3 ml) of 0.54 g(1S,5R,6R,7R)-2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S)-3-t-butyldimethylsiloxy-1-octynyl}-bicyclo[3.3.0]octan-3-oneprepared in step 1 was added thereto. This solution was cooled to -78°C., and the above lithium diisopropylamide solution was dropwise addedthereto at -78° C. The mixture was stirred for 20 minutes. Then, 0.38 gof N-fluorobenzenesulfonimide was added thereto at -78° C. The mixturewas stirred at -78° C. for 60 minutes and at room temperature for 30minutes. Then, the mixture was poured into a saturated sodium hydrogencarbonate aqueous solution, and the mixture was extracted with ethylacetate. The extract was purified by silica gel column chromatography(ethyl acetate:hexane=1:30 to 1:10) to obtain 0.43 g of theabove-identified compound.

¹ H-NMR (CDCl₃) δ (ppm): 0.04 (m, 12H), 0.89 (m, 21H), 1.0-5.4 (m, 15H).

¹⁹ F-NMR (CDCl₃, ppm): -92(dd, J=25, 280 Hz), -113 (d,J=280 Hz).

Step 3 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S)-3-t-butyldimethylsiloxy-1-octynyl}-bicyclo[3.3.0]octan-3-ylidene]pentanoate

A dry ethyl ether (8 ml) solution of 0.29 g of1-(4-iodobutyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (Compound 4)was cooled to -78° C., and 1.4 ml of t-butyl lithium (1.48 M, pentanesolution) was added thereto. The mixture was stirred at -78° C. for twohours. To this mixture, a THF solution (3 ml) of 0.44 g of(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S)-3-t-butyldimethylsiloxy-1-octynyl}bicyclo[3.3.0]octan-3-oneprepared in step 2 was added. Then, the mixture was stirred at -78° C.for one hour and at -60° C. for one hour, and then poured into anaqueous sodium carbonate solution. The mixture was extracted with ethylacetate. The extract solution was washed with a saturated sodiumchloride aqueous solution and then concentrated under reduced pressure.

To the residue, 3 ml of methylene chloride was added, and 0.79 ml oftriethylamine and 0.21 ml of methanesulfonyl chloride were added at 0°C. Then, the mixture was stirred at room temperature for 1.5 hours andthen poured into an aqueous sodium hydrogen carbonate solution. Themixture was extracted with ethyl acetate. The extract solution wasconcentrated under reduced pressure and purified by silica gel columnchromatography (ethyl acetate:hexane=1:30 to 1:10) to obtain 0.39 mg of(1S,5R,6R,7R)-2-oxa-{4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octanyl)butylidene)-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S)-3-t-butyldimethylsiloxy-1-octynyl}bicyclo[3.3.0]octane.To a dimethoxyethane (5 ml) solution thereof, 0.5 ml of a 10% sodiumhydrogen sulfate aqueous solution was added at 0° C., and the mixturewas stirred for 30 minutes. The mixture was poured into an aqueoussodium hydrogen carbonate solution, and the mixture was extracted withethyl acetate. The extract solution was concentrated under reducedpressure. To the residue, 5 ml of methanol and 0.19 g of potassiumcarbonate were added. The mixture was stirred at room temperature fortwo hours. The mixture was poured into an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethylacetate-hexane (1:1). The extract solution was concentrated underreduced pressure and purified by silica gel column chromatography (ethylacetate:hexane=1:30 to 1:10) to obtain 0.29 g of the above-identifiedcompound.

¹ H-NMR (CDCl₃) δ (ppm): 0.03-0.11 (m, 12H), 0.84-0.95 (m, 18H), 1.1-2.6(m, 21 H), 3.67 (s, 3H), 3.8-5.0 (m 4H).

¹⁹ F-NMR (CDCl₃, ppm): -83 (dd, J=249 Hz), -115 (d, J=249 Hz).

Step 4 Preparation of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-hydroxy-1-octynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 30)

To a THF (5 ml) solution of 284 mg of methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S)-3-t-butyldimethylsiloxy-1-octynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate,1.5 ml of tetrabutyl ammonium fluoride (1 M, THF solution) was added,and the mixture was stirred at room temperature for 18 hours. Thereaction solution was concentrated under reduced pressure and purifiedby silica gel column chromatography (acetone-methylene chloride) toobtain 140 mg of the above-identified compound.

¹ H-NMR (CDCl₃) δ (ppm): 0.9-3.0 (m, 21H), 3.66 (s, 3H), 3.8-5.0 (m,4H).

¹⁹ F-NMR (CDCl₃, ppm): -84 (dd, J=17, 248Hz), -116 (d, J=248 Hz).

EXAMPLE 39 Preparation of sodium5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-hydroxy-1-octynyl}bicyclo[3.3.0]octan-3-ylidene]pentanoate(Compound 31)

The above-identified compound was prepared by the same method as inExample 11 using methyl5-[(1S,5R,6R,7R)-2-oxa-4,4-difluoro-7-hydroxy-6-{(3S)-3-hydroxy-1-octynyl}bicyclo[3.3.0]octan-3ylidene]pentanoate(Compound 30) prepared in Example 38.

¹ H-NMR (D₂ O) δ (ppm) : 0.9-3.0 (m, 21H), 3.7-5.0 (m, 4H).

¹⁹ F-NMR (D₂ O, ppm): -84 (dd, J=17, 250 Hz), -116 (d, J=250 Hz).

EXAMPLE 40

Platelet aggregation inhibitory activities in vitro

Platelet aggregation inhibitory activities of test compounds in vitrowere measured by using human platelets.

Into a plastic container containing one volume of a 3.8% sodium citratesolution, 9 volumes of blood of a healthy person was collected, and thecontainer was gently turned over for admixing. The mixture wascentrifugally separated at 1,000 rpm for 10 minutes at room temperature,whereupon the supernatant was taken as a platelet-rich plasma (PRP). Thelower layer was further centrifugally separated at 3,000 rpm for 15minutes at room temperature, whereupon the supernatant was taken as aplatelet-poor plasma (PPP). PRP was diluted with PPP so that the numberof platelets became about 30×10⁴ /μl. An aggregometer was calibrated,and then 200 μl of PRP thus prepared was heated at 37° C. for oneminute. Then, 25 μl of a solution obtained by diluting a test compoundwith a physiological sodium chloride solution, was added thereto, andthe mixture was heated at 37° C. for one minute. Then, 25 ml of anadenosine-5═-1.5 sodium diphosphate (ADP, Sigma) solution was addedthereto so that the final concentration would be 4 μM, whereby thechange in transmittance was recorded by the aggregometer. Thetransmittance was measured with respect to the solution immediatelyafter dissolving the test compound in the physiological sodium chloridesolution and the solution after leaving it at 25° C. for 24 hours. Thesolution of the test compound was dissolved in a physiological sodiumchloride solution and then used by diluting it with a physiologicalsodium chloride solution. IC₅₀ (50% inhibitory concentration) was shownin Table 3.

    Aggregation inhibition (%)=(1-T/TO)×100

T0: Transmittance in the case where the physiological sodium chloridesolution was added.

T: Transmittance in the case where the test compound was added.

As shown in Table 3, it has been confirmed that the compounds of thepresent invention exhibit excellent platelet aggregation inhibitoryactivities, and yet they are remarkably stabilized compounds with theplatelet aggregation inhibitory activities which do not deteriorate evenafter 24 hours. Further, in particular, Compounds 11 and 27 of thepresent invention have activities close to natural type prostacyclin,and Compounds 15 and 17 of the present invention have even higheractivities than natural type prostacyclin. Compound 31 has lowactivities as compared with other compounds (11, 13, 15, 17, 19, 21, 23,25 and 27).

Compound 31 is 7,7-difluoro-13,14-dehydroprostacyclin disclosed inJapanese International Patent Publication No. 501319/1981, which wassynthesized anew by the process developed by the present inventors asdescribed in Examples 38 and 39. Further, PGI₂ Na represents a sodiumsalt of natural type prostacyclin.

                  TABLE 3                                                         ______________________________________                                                    IC.sub.50 (ng/ml)                                                               Immediately after                                                                          24 hours                                           Test compound preparation  later                                              ______________________________________                                        Compound 11   8.6          7.8                                                Compound 13   66.3         62.9                                               Compound 15   0.79         0.78                                               Compound 17   0.38         0.39                                               Compound 19   56.1         60.4                                               Compound 21   8.7          8.9                                                Compound 23   59.0         58.2                                               Compound 25   27.0         28.1                                               Compound 27   8.4          8.0                                                Compound 29   >200         >200                                               Compound 31   73.7         75.8                                               PGI.sub.2 Na  2.1          >200                                               ______________________________________                                    

EXAMPLE 41

Stability test in an aqueous solution A test compound was dissolved inethanol to a concentration of 1 mg/ml. Then, it was diluted with aphysiological sodium chloride solution to obtain a solution having aconcentration of 10 μg/ml. The solution was stored at 25° C., and theremaining ratio of the test compound was measured as time passed. Theremaining ratio was quantitatively analyzed by an internal standard(methyl benzoate) method using high performance liquid chromatography(Shimadzu LC9A, SPC-6AU; Milipore 805-DS). The column used was YMC AM312(ODS), and the eluent used was a solvent mixture of acetonitrile and a1% triethylamine-phosphoric acid buffer solution (pH 6.3).

In Table 4, the remaining ratio and the half-life were shown. As shownin Table 4, it has been confirmed that the compounds of the presentinvention exhibit excellent stability in their aqueous solutions.

                  TABLE 4                                                         ______________________________________                                                   Remaining ratio                                                    Test compound                                                                             7 days    20 days Half-life (days)                                ______________________________________                                        Compound 11 102.2     96.8    >90                                             Compound 13 100.4     98.0    >90                                             Compound 15 98.9      97.8    >90                                             Compound 17 101.5     100.1   >90                                             Compound 19 99.3      97.2    >90                                             Compound 21 101.2     100.5   >90                                             Compound 23 100.5     100.1   >90                                             Compound 25 101.0     99.8    >90                                             Compound 27 99.5      100.2   >90                                             Compound 29 99.1      99.3    >90                                             Compound 31 99.5      97.0    >90                                             ______________________________________                                    

What is claimed is:
 1. A difluoroprostacyclin of formula (IV): ##STR13##wherein A is an ethylene group, a vinylene group or an ethynylene group,R is a C₂₋₁₀ alkynyl group, Q is a monovalent organic group of theformula -B-Z, where B is a bivalent organic group and Z is a carboxylgroup, a group which can be converted to a carboxyl group, a formylgroup, a protected formyl group, a hydroxyl group, or a protectedhydroxyl group, and each of R¹ and R³ which are independent of eachother, is a hydrogen atom or a protecting group for a hydroxyl group ora pharmaceutically acceptable salt thereof.
 2. The difluoroprostacyclinof claim 1, wherein R is a C₄₋₁₀ alkynyl group.
 3. Thedifluoroprostacyclin of claim 1, wherein B is a lower alkylene group, alower cycloalkylene group, a lower alkylene group containing a lowercycloalkylene group, a lower alkylene group containing an ether bond ora thioether bond, or a phenylene group.
 4. The difluoroprostacyclin ofclaim 3, wherein B is a C₃₋₅ alkylene group.
 5. The difluoroprostacyclinof claim 2, wherein Z is a carboxyl group or a group which can beconverted to a carboxyl group.
 6. The difluoroprostacyclin of claim 2,wherein Z is a formyl group or a protected formyl group.
 7. Thedifluoroprostacyclin of claim 2, wherein Z is a hydroxyl group or aprotected hydroxyl group.
 8. The difluoroprostacyclin of claim 1, havingformula (V) ##STR14## wherein A and R are as defined above.
 9. Thedifluoroprostacyclin of claim 8, wherein A is a vinylene group and R isa C₄₋₁₀ alkynyl group.
 10. The difluoroprostacyclin of claim 1, whereinR is a 3-hydroxy-4-methyl-E-1-nonen-6-ynyl group.
 11. Thedifluoroprostacyclin of claim 1, wherein said group which can beconverted to a carboxyl group is a carboxyl group neutralized with abase, an esterified carboxyl group, an orthoesterified carboxyl group,an amide-modified carboxyl group or a carboxyl group protected by atetrazole or a nitrile.
 12. A pharmaceutical composition for acirculatory system disorder, comprising the difluoroprostacyclin ofclaim 1, and a pharmaceutically acceptable carrier or diluent.
 13. Apharmaceutical composition for a circulatory system disorder, comprisingthe difluoroprostacyclin of claim 8, and a pharmaceutically acceptablecarrier or diluent.